Literature report for BIBW2992
Contents
Related concepts
Facts with concepts
Wordclouds
Statements
References

Introduction
This report provides an overview of the most relevant scientific literature for BIBW2992. This overview is generated based on the occurrence of BIBW2992 and its synonyms in MEDLINE abstracts together with concepts from a number of other ontologies. This is done in a number of ways, shortly described below and described in more details in the respective sections.
  • Based on the occurrence of BIBW2992 in these abstracts, other biomedical terms, related to diseases, drugs and pathways that occur in the same abstracts as BIBW2992 are retrieved.
  • In addition, the abstracts are scanned for other informative words and visualised in wordclouds.
  • Furthermore, important sentences and facts for BIBW2992 are retrieved and shown in a separate table with a link to the original abstracts.
  • Lastly the most relevant abstracts are shown in which BIBW2992 and it's synomyms are highlighted.

This report is an interactive HTML report.The hyperlinks in this document link to other sections in the document or to external data sources (which will be opened in a separate window). Most of the tables have options for filtering, searching and exporting the data to Excel.


Related concepts
The following tables show the relation of BIBW2992 with biomedical terms representing genes, diseases and pathways. Each relation is described by the number of abstracts in which both terms co-occur and a statistical score. The relations to other genes were obtained by matching to concepts from the human genes database from the website of the Human Genome Nomenclature Committee. The disease concepts for matching were obtained from the Human Disease Ontology website. The ontologies for Drugs and Pathways are TenWise proprietary ontologies (see this page for more information).

Concept ID Hits Score Link
obsolete neck cancerDOID:111211.5Pubmed
lung carcinomaDOID:390511.5Pubmed
lung non-small cell carcinomaDOID:3908152.2Pubmed
malariaDOID:1236510.9Pubmed
echinococcosisDOID:149611.7Pubmed
ovarian cancerDOID:239421.4Pubmed
lung adenocarcinomaDOID:391032.1Pubmed
melanomaDOID:190910.7Pubmed
breast cancerDOID:161241.0Pubmed
head and neck carcinomaDOID:154212.6Pubmed
osteosarcomaDOID:334711.4Pubmed
yellow feverDOID:968212.0Pubmed
meningitisDOID:947111.1Pubmed
adenocarcinomaDOID:29941.3Pubmed
alveolar echinococcosisDOID:1214812.6Pubmed
Concept ID Hits Score Link
EGFRHGNC:3236262.7Pubmed
DMPKHGNC:293312.5Pubmed
BRAFHGNC:109711.8Pubmed
PRKAA2HGNC:937711.7Pubmed
STAT3HGNC:1136411.5Pubmed
PARP1HGNC:27011.7Pubmed
HGFHGNC:489311.9Pubmed
METHGNC:702932.4Pubmed
EGFHGNC:322931.9Pubmed
AKT1HGNC:39121.8Pubmed
MCL1HGNC:694312.1Pubmed
IGF1RHGNC:546532.6Pubmed
KRASHGNC:640711.8Pubmed
HDAC9HGNC:1406511.9Pubmed
NKS1HGNC:783214.1Pubmed
Concept ID Hits Score Link
AKT-mTOR signallingPATH_00242712.1Pubmed
mTOR signallingPATH_00169822.1Pubmed
EGFR signallingPATH_00243532.7Pubmed
Akt signallingPATH_00168721.8Pubmed
ERK signallingPATH_00168922.1Pubmed
glycolysisPATH_00166711.3Pubmed
apoptosisPATH_00001281.2Pubmed
glucose metabolismPATH_00005611.3Pubmed
autophagyPATH_00249611.2Pubmed
ERBB signallingPATH_00171013.0Pubmed
PI3K-AKT signallingPATH_00165522.1Pubmed
MEK-ERK signallingPATH_00165012.4Pubmed
AMPK-mTOR signallingPATH_00245813.2Pubmed
Concept ID Hits Score Link
Stomach cancerHP:001212621.3Pubmed
RecurrentHP:003179610.3Pubmed
Triggered byHP:002520411.1Pubmed
Breast carcinomaHP:000300241.0Pubmed
CarcinomaHP:003073140.6Pubmed
GliomaHP:000973311.2Pubmed
NeoplasmHP:0002664290.9Pubmed
OsteosarcomaHP:000266911.4Pubmed
DistalHP:001283910.4Pubmed
Ovarian neoplasmHP:010061521.3Pubmed
Lung adenocarcinomaHP:003007832.1Pubmed
FeverHP:000194510.6Pubmed
Neoplasm of the lungHP:0100526171.8Pubmed
Non-small cell lung carcinomaHP:0030358132.2Pubmed
Squamous cell carcinomaHP:000286021.2Pubmed
Concept ID Hits Score Link
Shigella dysenteriaeTAX_62212.6Pubmed
Lactobacillus rhamnosusTAX_4771512.4Pubmed
Echinococcus multilocularisTAX_621112.6Pubmed

Facts from sentences
The abstracts where BIBW2992 is described with other genes, diseases and pathways can be further analyzed to retrieve the exact sentences in which these concepts co-occur with BIBW2992. These are shown in the tables below. In each sentence the concepts are highlighted in bold and a link to the abstract in which the sentence was found is provided.

PMIDFACT
17235418AE-37, albumin interferon alfa, alicaforsen sodium, alvocidib hydrochloride, AMG-706, arginine butyrate, avanafil, axitinib, azimilide hydrochloride; BAY-579352, belagenpumatucel-L, beta-lapachone, BHT-3009, BIBW-2992, bremelanotide, BX-471; Casopitant mesylate, cediranib, certolizumab pegol, CH-1504, ChimeriVax-West Nile, clofazimine, CpG-7909, curcumin, Cypher; Dapoxetine hydrochloride, darusentan, diflomotecan, D-methionine, dnaJP1, D-serine, DTPw-HB Hib-MenAC, DTPw-HepB-Hib; E-7010, ecogramostim, edodekin alfa, EGFRvlll peptide vaccine, elcometrine, elcometrine/ethinylestradiol, elsilimomab, enrasentan, ertumaxomab, etalocib sodium, exisulind; Fenretinide, fesoterodine, fingolimod hydrochloride, fontolizumab; Gefitinib, gemtuzumab ozogamicin, ghrelin (human), GV-1001; HTU-PA, human papillomavirus vaccine; Indacaterol, indiplon, interleukin-21, intranasal insulin, irinotecan hydrochloride/floxuridine, ISIS-301012, ispinesib mesylate, ixabepilone; K562/GM-CSF; Lapatinib, L-BLP-25, linezolid, liposome encapsulated paclitaxel, LY-2124275; MC-1, MC-1/lisinopril, MDX-066, melanoma vaccine, MMR-V, multivalent (ACYW) meningitis vaccine; Nilotinib, nobori, nociceptin; Oblimersen sodium, orbofiban acetate, ospemifene; Paliperidone, panitumumab, PEG-filgrastim, PEGylated interferon alfacon-1, perflubutane, pertuzumab, phenserine tartrate, phVEGF-A165, pleconaril, prasugrel, prednisolone sodium metasulfobenzoate; R-411, recombinant malaria vaccine, rhGM-CSF, roflumilast, romidepsin, ruboxistaurin mesilate hydrate; Sirolimus-eluting stent, SR-4554, St.
24842595We aimed to investigate the inhibitory effects of a combination of BIBW2992 (irreversible EGFR inhibitor)/ARQ 197 (MET inhibitor) on the human lung adenocarcinoma cell line H1975.
19037840At the time of publication, BIBW-2992 was undergoing phase II trials for NSCLC, breast and prostate cancers, head and neck carcinoma, as well as glioma.
20530710We have now investigated the effects of combination treatment with thymidylate synthase (TS)-targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation.
20530710The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis.
20530710The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo.
20530710The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents.
20530710The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone.
31262325Moreover, BEZ235 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells by enhancing or prolonging DNA damage and BIBW2992-induced apoptosis in EGFR-TKI-resistant NSCLC cells containing a second TKI-resistant EGFR mutant.
19037840In phase I/II trials, BIBW-2992 was effective in patients with solid tumors, including those with NSCLC tumors activating mutations in the EGFR tyrosine kinase domain.
23091447Efficacies of gefitinib and BIBW2992 on osteosarcoma cells were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.
25384171Catenin knockdown enhanced the antitumor effect of BIBW2992 in the EGFR-mutated NSCLC cell line carrying the T790M mutation.
23091447CONCLUSION: In the present study, gefitinib and BIBW2992 were not effective against osteosarcoma cells.
19122144Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.
20530710BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy.
19037840BIBW-2992 was granted Fast-Track status by the FDA for NSCLC and was investigated in phase III trials for this indication.
PMIDFACT
24842595The BIBW2992/ARQ 197 combination significantly inhibited growth, induced cell cycle arrest and apoptosis, and altered the phosphorylation of EGFR, MET, AKT and ERK1/2 in the H1975 cells.
24842595We aimed to investigate the inhibitory effects of a combination of BIBW2992 (irreversible EGFR inhibitor)/ARQ 197 (MET inhibitor) on the human lung adenocarcinoma cell line H1975.
19037840The anilino-quinazoline derivative BIBW-2992, which is being developed by Boehringer Ingelheim Corp for the potential treatment of solid tumors, is an oral dual receptor tyrosine kinase inhibitor of human EGF receptor (EGFR) and human epidermal growth factor receptor-2 (HER-2)/neu.
25382705In the present study, we assessed whether the combination of suberoylanilide hydroxamic acid (SAHA, vorinostat), a potent HDAC inhibitor, and BIBW2992 or WZ4002 could overcome EGFR TKI resistance associated with T790M mutation in lung cancer cells.
22317763EXPERIMENTAL DESIGN: The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation.
19759520We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab.
20530710We have now investigated the effects of combination treatment with thymidylate synthase (TS)-targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation.
25382705To overcome T790M-mediated acquired resistance of lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), second generation TKIs such as BIBW2992 (afatinib) and third generation TKIs including WZ4002 have been developed.
18408761These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.
20530710The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis.
31262325The combination indexes of BEZ235 with cisplatin or an EGFR-TKI, BIBW2992 (afatinib), were calculated.
22135232PF00299804 showed significant growth-inhibitory effects in HER2-amplified gastric cancer cells (SNU216, N87), and it had lower 50% inhibitory concentration values compared with other EGFR tyrosine kinase inhibitors, including gefitinib, lapatinib, BIBW-2992, and CI-1033.
17208435Other agents include BIBW-2992 and HKI-272, irreversible TKIs of EGFR and HER2, and pertuzumab, a heterodimerisation inhibitor of EGFR and HER2.
31262325Moreover, BEZ235 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells by enhancing or prolonging DNA damage and BIBW2992-induced apoptosis in EGFR-TKI-resistant NSCLC cells containing a second TKI-resistant EGFR mutant.
28241017Inhibition of the signaling by either the EGFR inhibitors CI-1033 and BIBW2992 or the MEK/ERK inhibitor U0126 impairs germinative cell proliferation and larval growth.
19037840In vitro, BIBW-2992 effectively and selectively inhibited EGFR and HER-2/neu and inhibited EGFR and HER-2/neu total tyrosine phosphorylation and tumor cell proliferation in vivo.
19037840In phase I/II trials, BIBW-2992 was effective in patients with solid tumors, including those with NSCLC tumors activating mutations in the EGFR tyrosine kinase domain.
27373506In contrast to first generation EGFR inhibitors, afatinib (BIBW2992) is a second-generation irreversible ErbB family blocker that inhibits EGFR as well as HER2 and HER4.
19037840Importantly, BIBW-2992 was active against tumors overexpressing EGFR with the secondary Thr790Met point mutation, which confers resistance to the first-generation EGFR inhibitors gefitinib and erlotinib.
20718710However, novel irreversible EGFR inhibitors such as BIBW-2992 and HKI-272 may retain activity in tumours with T790M mutations.
18408761Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms.
24842595H1975 cells (harboring a T790M mutation in EGFR) were treated with erlotinib, BIBW2992 or ARQ 197 separately or with combinations of erlotinib/ARQ 197 or BIBW2992/ARQ 197.
24594844Combined treatment with cDzT and BIBW-2992, a second-generation EGFR-tyrosine kinase inhibitor, synergistically inhibited EGFR downstream signaling and suppressed the growth of xenograft tumors derived from H1975(TM/LR) cells.
25384171Catenin knockdown enhanced the antitumor effect of BIBW2992 in the EGFR-mutated NSCLC cell line carrying the T790M mutation.
18520300BIBW2992 is an irreversible EGFR TKI that also inhibits HER2 and vascular epidermal growth factor receptors.
23883584Although afatinib (BIBW2992), a second-generation irreversible EGFR-TKI, was expected to overcome the acquired resistance, it showed limited efficacy in a recent phase III clinical study.
21791633Afatinib (BIBW-2992), an irreversible kinase inhibitor targeting EGFR and HER2, successfully inhibited growth of the cetuximab-resistant cells in vitro.
PMIDFACT
19122144Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways.
25382705While treatment with BIBW2992 or WZ4002 alone slightly reduced the viability of PC-9G and H1975 cells, which possess T790M mutation, combining them with SAHA resulted in significantly decreased cell viability through the activation of the apoptotic pathway.
20530710The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis.
24842595The BIBW2992/ARQ 197 combination significantly inhibited growth, induced cell cycle arrest and apoptosis, and altered the phosphorylation of EGFR, MET, AKT and ERK1/2 in the H1975 cells.
31262325Moreover, BEZ235 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells by enhancing or prolonging DNA damage and BIBW2992-induced apoptosis in EGFR-TKI-resistant NSCLC cells containing a second TKI-resistant EGFR mutant.
20103621Combined treatment of T790M-mutant tumor cells with BIBW-2992 and the phosphoinositide-3-kinase/mammalian target of rapamycin inhibitor PI-103 led to synergistic induction of apoptosis.
PMIDFACT
18408761Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib.
19122144Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.
25382705To overcome T790M-mediated acquired resistance of lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), second generation TKIs such as BIBW2992 (afatinib) and third generation TKIs including WZ4002 have been developed.
18408761These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.
22135232PF00299804 showed significant growth-inhibitory effects in HER2-amplified gastric cancer cells (SNU216, N87), and it had lower 50% inhibitory concentration values compared with other EGFR tyrosine kinase inhibitors, including gefitinib, lapatinib, BIBW-2992, and CI-1033.
25382705In the present study, we assessed whether the combination of suberoylanilide hydroxamic acid (SAHA, vorinostat), a potent HDAC inhibitor, and BIBW2992 or WZ4002 could overcome EGFR TKI resistance associated with T790M mutation in lung cancer cells.
22317763EXPERIMENTAL DESIGN: The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation.
19037840At the time of publication, BIBW-2992 was undergoing phase II trials for NSCLC, breast and prostate cancers, head and neck carcinoma, as well as glioma.
24842595We aimed to investigate the inhibitory effects of a combination of BIBW2992 (irreversible EGFR inhibitor)/ARQ 197 (MET inhibitor) on the human lung adenocarcinoma cell line H1975.
31262325The anti-tumor effect of BEZ235 alone or combined with cisplatin or BIBW2992 were also studied in vivo.
19122144Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2(YVMA) transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage.
19037840In vitro, BIBW-2992 effectively and selectively inhibited EGFR and HER-2/neu and inhibited EGFR and HER-2/neu total tyrosine phosphorylation and tumor cell proliferation in vivo.
25382705Finally, the combined treatment with SAHA and either BIBW2992 or WZ4002 showed an enhanced anti-tumor effect on xenografts of H1975 cells in vivo.
23091447Efficacies of gefitinib and BIBW2992 on osteosarcoma cells were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.
20103621Combined treatment of T790M-mutant tumor cells with BIBW-2992 and the phosphoinositide-3-kinase/mammalian target of rapamycin inhibitor PI-103 led to synergistic induction of apoptosis.
23091447CONCLUSION: In the present study, gefitinib and BIBW2992 were not effective against osteosarcoma cells.
PMIDFACT
18773127D10, 9vPnC-MnCc; Adalimumab, Adefovir dipivoxil, Alefacept, ALN-RSV01, AME-133, AMG-317, Aminolevulinic acid methyl ester, Amlodipine besylate/atorvastatin calcium, Anisodamine, Anti-IL-5 receptor antibody, Apremilast, Aripiprazole, Atacicept, Atazanavir sulfate, Atrasentan; Banoxantrone, Bevacizumab, BIBW-2992, Binodenoson, BMS-387032; cAC10, Caldaret hydrate, CD-NP, Ceftobiprole medocaril, Celivarone fumarate, Certolizumab pegol, Cholesteryl hydrophobized polysaccharide-Her2 protein complex, Choline fenofibrate, Cilengitide, Cinaciguat, Curcumin, Custirsen sodium, Cypher, CYT-6091; Dalcetrapib, Deforolimus, Desvenlafaxine succinate, DHA-paclitaxel, DP6-001; E-7010, E75, Ecogramostim, EGF-P64K, EnvPro, Enzastaurin hydrochloride, Escitalopram oxalate, Ezetimibe, Ezetimibe/simvastatin; Fenretinide; Gefitinib, Golimumab, Green tea catechins, GTI-2040, GW-406381; HPV16 E6 E7, HPV-16/18 AS04, HPV-6/11/16/18; ICC-1132, Immune globulin intravenous (human), Indacaterol, Intranasal insulin; Kahalalide F; Lactobacillus rhamnosus, Laromustine, Laropiprant, GTI-2040; MAb 3H1, Mepolizumab, Mifamurtide, Milataxel, MP4; Nebicapone, Nelarabine, Neuradiab; Oncolytic HSV; PCV7, PHX-1149, Pimecrolimus, Pralatrexate, Pramiconazole; Ranibizumab, Reolysin, Rilonacept, Rolofylline, Romidepsin; S-32865, Shigella dysenteriae 1 vaccine; Taranabant, Taxus, TZP-101; Ustekinumab; Vitespen; Zileuton, Zycure.

Wordcloud
To generate a word cloud, a large number of abstracts for BIBW2992 are retrieved and analysed for frequently occurring words. Words that are common and non-informative, such as ‘the’, ’and’, ‘this’ etc. (also called stop words), are removed from the word clouds before visualisation. All terms in the word cloud are hyperlinked to PubMed which means that if you click on a term, the corresponding search page in PubMed is opened with that search term combined with the BIBW2992 term.

Ecogramostim HNSCC Preclinical Lapatinib Bevacizumab HM781 Ezetimibe Aliskiren H1975 Golimumab Afatinib Rosuvastatin Everolimus Cediranib XAV939 Taxus Adalimumab PF00299804 Rolofylline Oblimersen Denosumab Vorinostat Adefovir PIK3CA XL647 Gefitinib Sorafenib Amlodipine Paliperidone Certolizumab T790M Laropiprant Trials HKESC Tenofovir Ipilimumab Tolvaptan NSCLC Liposomal WZ4002 Valsartan Rivaroxaban BEZ235 Enzastaurin Cypher L858R E7050 Deforolimus BIBW2992 Peginterferon Prasugrel Zotarolimus Catenin Fenretinide IGF1R Vatalanib Telmisartan Bortezomib Rilonacept HCC827

Statements
The following section contains a list of sentences that contain the term BIBW2992 or one of its synonyms. The sentences are ordered based on the abstracts from which they were retrieved. The highlighted link in the first column is linked to the abstract in PubMed. The search button in the top right can be used to only show sentences with a particular additional keyword.

PMIDNRSENT FACT
17922073 1 In]-DOTA-cG250, [131I]-Metuximab injection, [177Lu]-DOTA-cG250; Anatumomab mafenatox, AP-12009; BIBW-2992, Biricodar dicitrate; Cediranib, Cilengitide, Clevidipine, CNTO-528, CNTO-95, CP-870893; Disufenton sodium, DNK-333A; Ecallantide, Enzastaurin hydrochloride, Etravirine, Exatecan mesilate; Fingolimod hydrochloride; Human insulin, Hyaluronic acid; Indisulam, Inhaled insulin, Insulin glargine, Ipilimumab, Irofulven, Ispronicline, ITF-282; J591; KAI-9803; L-Arginine hydrochloride, Laropiprant, LY-518674; Matuzumab, MB-7133, Methylnaltrexone bromide, MVA-5T4; Nemifitide ditriflutate; Obatoclax mesylate, Oral insulin; P-276-00, PF-562271, Picolinic acid; Quercetin; R-109339, R-547, Rivaroxaban, Ruboxistaurin mesilate hydrate; Seliciclib; Terameprocol, Tilarginine hydrochloride, Tolvaptan, Uracil; Vincristine.
23091447 2 CONCLUSION: In the present study, gefitinib and BIBW2992 were not effective against osteosarcoma cells.
23091447 1 Efficacies of gefitinib and BIBW2992 on osteosarcoma cells were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.
27373506 1 In contrast to first generation EGFR inhibitors, afatinib (BIBW2992) is a second-generation irreversible ErbB family blocker that inhibits EGFR as well as HER2 and HER4.
18520300 2 The preliminary results from phase I and phase II trials for BIBW-2992 and XL647 are discussed.
18520300 1 BIBW2992 is an irreversible EGFR TKI that also inhibits HER2 and vascular epidermal growth factor receptors.
17208435 1 Other agents include BIBW-2992 and HKI-272, irreversible TKIs of EGFR and HER2, and pertuzumab, a heterodimerisation inhibitor of EGFR and HER2.
20103621 1 Combined treatment of T790M-mutant tumor cells with BIBW-2992 and the phosphoinositide-3-kinase/mammalian target of rapamycin inhibitor PI-103 led to synergistic induction of apoptosis.
28241017 1 Inhibition of the signaling by either the EGFR inhibitors CI-1033 and BIBW2992 or the MEK/ERK inhibitor U0126 impairs germinative cell proliferation and larval growth.
18597009 1 IFN-beta, AF-37702, Agatolimod sodium, Agomelatine, Alvocidib hydrochloride, ARC-1779; Belimumab, BIBW-2992, Binodenoson, Bortezomib, Bosutinib, Brivaracetam; Cediranib, Clevidipine, CNTO-328, CP-751871, Curcumin; Darapladib, Deforolimus, Denosumab, Desvenlafaxine succinate, Dipyridamole/prednisolone, Dronedarone hydrochloride, DTPw-HBV/Hib 2.
22317763 1 EXPERIMENTAL DESIGN: The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation.
22135232 1 PF00299804 showed significant growth-inhibitory effects in HER2-amplified gastric cancer cells (SNU216, N87), and it had lower 50% inhibitory concentration values compared with other EGFR tyrosine kinase inhibitors, including gefitinib, lapatinib, BIBW-2992, and CI-1033.
20718710 1 However, novel irreversible EGFR inhibitors such as BIBW-2992 and HKI-272 may retain activity in tumours with T790M mutations.
29383145 1 Five drugs (ABT-888, BIBW2992, gefitinib, AZD6244 and lenalidomide) exhibit higher efficacy in SOC resistant ovarian tumors when multi-platform of transcriptome profiling methods were employed.
24842595 1 We aimed to investigate the inhibitory effects of a combination of BIBW2992 (irreversible EGFR inhibitor)/ARQ 197 (MET inhibitor) on the human lung adenocarcinoma cell line H1975.
19122144 3 Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.
19122144 2 Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways.
19122144 1 Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2(YVMA) transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage.
21791633 1 Afatinib (BIBW-2992), an irreversible kinase inhibitor targeting EGFR and HER2, successfully inhibited growth of the cetuximab-resistant cells in vitro.
19759520 1 We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab.
25382705 1 To overcome T790M-mediated acquired resistance of lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), second generation TKIs such as BIBW2992 (afatinib) and third generation TKIs including WZ4002 have been developed.
25428177 1 Four drugs, Bosutinib, Docetaxel, BIBW2992, and Gefitinib, were found via multiple-test corrected ANOVA to have lower IC50 values, suggesting higher drug sensitivity, in HNSCC lines versus non-HNSCC lines.
25382705 3 While treatment with BIBW2992 or WZ4002 alone slightly reduced the viability of PC-9G and H1975 cells, which possess T790M mutation, combining them with SAHA resulted in significantly decreased cell viability through the activation of the apoptotic pathway.
25382705 2 In the present study, we assessed whether the combination of suberoylanilide hydroxamic acid (SAHA, vorinostat), a potent HDAC inhibitor, and BIBW2992 or WZ4002 could overcome EGFR TKI resistance associated with T790M mutation in lung cancer cells.
25382705 5 Finally, the combined treatment with SAHA and either BIBW2992 or WZ4002 showed an enhanced anti-tumor effect on xenografts of H1975 cells in vivo.
25382705 4 Caspase-independent autophagic cell death was also induced by the combination treatment with SAHA and either BIBW2992 or WZ4002.
18408761 1 Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms.
18408761 2 Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib.
18408761 3 These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.
23883584 1 Although afatinib (BIBW2992), a second-generation irreversible EGFR-TKI, was expected to overcome the acquired resistance, it showed limited efficacy in a recent phase III clinical study.
31262325 1 The combination indexes of BEZ235 with cisplatin or an EGFR-TKI, BIBW2992 (afatinib), were calculated.
31262325 3 Moreover, BEZ235 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells by enhancing or prolonging DNA damage and BIBW2992-induced apoptosis in EGFR-TKI-resistant NSCLC cells containing a second TKI-resistant EGFR mutant.
31262325 2 The anti-tumor effect of BEZ235 alone or combined with cisplatin or BIBW2992 were also studied in vivo.
24594844 1 Combined treatment with cDzT and BIBW-2992, a second-generation EGFR-tyrosine kinase inhibitor, synergistically inhibited EGFR downstream signaling and suppressed the growth of xenograft tumors derived from H1975(TM/LR) cells.
24842595 2 H1975 cells (harboring a T790M mutation in EGFR) were treated with erlotinib, BIBW2992 or ARQ 197 separately or with combinations of erlotinib/ARQ 197 or BIBW2992/ARQ 197.
24842595 3 The BIBW2992/ARQ 197 combination significantly inhibited growth, induced cell cycle arrest and apoptosis, and altered the phosphorylation of EGFR, MET, AKT and ERK1/2 in the H1975 cells.
19037840 7 BIBW-2992 was granted Fast-Track status by the FDA for NSCLC and was investigated in phase III trials for this indication.
19037840 6 At the time of publication, BIBW-2992 was undergoing phase II trials for NSCLC, breast and prostate cancers, head and neck carcinoma, as well as glioma.
19037840 5 BIBW-2992 was generally well tolerated with the main adverse effects being gastrointestinal or cutaneous disorders.
19037840 4 In phase I/II trials, BIBW-2992 was effective in patients with solid tumors, including those with NSCLC tumors activating mutations in the EGFR tyrosine kinase domain.
19037840 3 Importantly, BIBW-2992 was active against tumors overexpressing EGFR with the secondary Thr790Met point mutation, which confers resistance to the first-generation EGFR inhibitors gefitinib and erlotinib.
19037840 2 In vitro, BIBW-2992 effectively and selectively inhibited EGFR and HER-2/neu and inhibited EGFR and HER-2/neu total tyrosine phosphorylation and tumor cell proliferation in vivo.
19037840 1 The anilino-quinazoline derivative BIBW-2992, which is being developed by Boehringer Ingelheim Corp for the potential treatment of solid tumors, is an oral dual receptor tyrosine kinase inhibitor of human EGF receptor (EGFR) and human epidermal growth factor receptor-2 (HER-2)/neu.
17235418 1 AE-37, albumin interferon alfa, alicaforsen sodium, alvocidib hydrochloride, AMG-706, arginine butyrate, avanafil, axitinib, azimilide hydrochloride; BAY-579352, belagenpumatucel-L, beta-lapachone, BHT-3009, BIBW-2992, bremelanotide, BX-471; Casopitant mesylate, cediranib, certolizumab pegol, CH-1504, ChimeriVax-West Nile, clofazimine, CpG-7909, curcumin, Cypher; Dapoxetine hydrochloride, darusentan, diflomotecan, D-methionine, dnaJP1, D-serine, DTPw-HB Hib-MenAC, DTPw-HepB-Hib; E-7010, ecogramostim, edodekin alfa, EGFRvlll peptide vaccine, elcometrine, elcometrine/ethinylestradiol, elsilimomab, enrasentan, ertumaxomab, etalocib sodium, exisulind; Fenretinide, fesoterodine, fingolimod hydrochloride, fontolizumab; Gefitinib, gemtuzumab ozogamicin, ghrelin (human), GV-1001; HTU-PA, human papillomavirus vaccine; Indacaterol, indiplon, interleukin-21, intranasal insulin, irinotecan hydrochloride/floxuridine, ISIS-301012, ispinesib mesylate, ixabepilone; K562/GM-CSF; Lapatinib, L-BLP-25, linezolid, liposome encapsulated paclitaxel, LY-2124275; MC-1, MC-1/lisinopril, MDX-066, melanoma vaccine, MMR-V, multivalent (ACYW) meningitis vaccine; Nilotinib, nobori, nociceptin; Oblimersen sodium, orbofiban acetate, ospemifene; Paliperidone, panitumumab, PEG-filgrastim, PEGylated interferon alfacon-1, perflubutane, pertuzumab, phenserine tartrate, phVEGF-A165, pleconaril, prasugrel, prednisolone sodium metasulfobenzoate; R-411, recombinant malaria vaccine, rhGM-CSF, roflumilast, romidepsin, ruboxistaurin mesilate hydrate; Sirolimus-eluting stent, SR-4554, St.
20530710 5 BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy.
20508873 1 Benzylguanine; (-)-Gossypol; Abatacept, AC-2592, Adalimumab, AIDSVAX gp120 B/E, Alemtuzumab, Aliskiren fumarate, ALVAC E120TMG, Ambrisentan, Amlodipine, Anakinra, Aripiprazole, Armodafinil, Atomoxetine hydrochloride, Avotermin; Bevacizumab, BIBW-2992, Bortezomib, Bosentan, Botulinum toxin type B; Canakinumab, CAT-354, Ciclesonide, CMV gB vaccine, Corifollitropin alfa, Daptomycin, Darbepoetin alfa, Dasatinib, Denosumab; EndoTAG-1, Eplerenone, Esomeprazole sodium, Eszopiclone, Etoricoxib, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; F-50040, Fesoterodine fumavate, Fondaparinux sodium, Fulvestrant; Gabapentin enacarbil, Golimumab; Imatinib mesylate, Inhalable human insulin, Insulin glargine, Ivabradine hydrochloride; Lercanidipine hydrochloride/enalapril maleate, Levosimendan, Liposomal vincristine sulfate, Liraglutide; MDV-3100, Mometasone furoate/formoterol fumavate, Multiepitope CTL peptide vaccine, Mycophenolic acid sodium salt, Nabiximols, Natalizumab, Nesiritide; Obeticholic acid, Olmesartan medoxomil, Omalizumab, Omecamtiv mecarbil; Paclitaxel-eluting stent, Paliperidone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, Polymyxin B nonapeptide, PORxin-302, Prasugrel, Pregabalin, Pridopidine; Ranelic acid distrontium salt, Rasagiline mesilate, rDEN4delta30-4995, Recombinant human relaxin H2, rhFSH, Rilonacept, Rolofylline, Rosiglitazone maleate/metformin hydrochloride, Rosuvastatin calcium, Rotigotine; Salcaprozic acid sodium salt, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, Sitaxentan sodium, Sorafenib, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, Temsirolimus, Tenofovir, Tenofovir disoproxil fumarate, Teriparatide, Tiotropium bromide, Tocilizumab, Tolvaptan, Tozasertib, Treprostinil sodium; Ustekinumab; Vardenafil hydrochloride hydrate, Varenicline tartrate, Vatalanib succinate, Voriconazole, Vorinostat; Zotarolimus-eluting stent.
20530710 6 The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone.
20530710 1 We have now investigated the effects of combination treatment with thymidylate synthase (TS)-targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation.
20530710 3 The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo.
20530710 2 The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis.
25384171 1 Catenin knockdown enhanced the antitumor effect of BIBW2992 in the EGFR-mutated NSCLC cell line carrying the T790M mutation.
18850047 1 Epigallocatechin gallate, 501516, 89-12; Abatacept, Adalimumab, Adefovir dipivoxil, AG-701, Agatolimod sodium, Alefacept, Aliskiren fumarate, Apixaban, Atazanavir sulfate, Atrasentan, Axitinib; BI-1744-CL, BIBF-1120, BIBW-2992, Bortezomib; Carboxyamidotriazole, Caspofungin acetate, CBP-501, Cediranib, Ceftobiprole, Certolizumab pegol, Cetuximab, Cholesteryl hydrophobized polysaccharide-Her2 protein complex, CHP-NY-ESO-1, Cypher; Dalbavancin, Dalcetrapib, Daptomycin, Darapladib, Deferasirox, Deforolimus, Denosumab, DNA-HIV-C, Dovitinib, DR-5001, Dronedarone hydrochloride, DT388IL3; E75, EC-17/EC-90, Ecogramostim, Efungumab, Entecavir, EP HIV-1090, EP-2101, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Faropenem daloxate, Fluticasone furoate, Fondaparinux sodium, Fospropofol disodium, Fulvestrant; Golimumab, GSK-089, GW-590735; HO/03/03, hTERT572, hTERT572Y; Iloperidone; Immunoglobulin intravenous (human), Ispinesib mesylate, Istradefylline, Ixabepilone; JR-031, JX-594; KLH; Laropiprant, Lecozotan hydrochloride, Lenalidomide, Lestaurtinib, Linezolid; MGCD-0103, MK-0646, MVA-BN Measles; NI-0401, Niacin/laropiprant, NSC-719239, NYVAC-C; Ospemifene; Paliperidone palmitate, PAN-811, PCV7, Pegfilgrastim, Peginterferon alfa-2a, PEGirinotecan, Perifosine, Pertuzumab, PF-00299804, Picoplatin, Pimavanserin tartrate, Pitavastatin calcium, Pomalidomide, Prasterone, Pratosartan, Prucalopride, PSMA27/pDOM, Pyridoxal phosphate; QS-21, Quercetin; Rebimastat, Rimonabant, Rolofylline, Romidepsin, Rosuvastatin calcium, RTS,S/SBAS2; SCH-530348, SN-29244, Soblidotin, Sodium dichloroacetate, Solifenacin succinate, Sorafenib, Spheramine, SU-6668, Succinobucol; Taranabant, Taxus, Telaprevir, Telavancin hydrochloride, Telbivudine, Tenofovir disoproxil fumarate, Tigecycline, Tiotropium bromide, Tocilizumab, Triphendiol; UC-781, Udenafil, UNIL-025; V-5 Immunitor, Valsartan/amlodipine besylate, Varenicline tartrate, Velafermin, Vernakalant hydrochloride, Vinflunine, Vitespen, Vorinostat, VX-001; Xience V, XRP-0038; Yttrium Y90 Epratuzumab; Z-360, Ziconotide, Ziprasidone hydrochloride, Zotarolimus, Zotarolimus-eluting stent.
18773127 1 D10, 9vPnC-MnCc; Adalimumab, Adefovir dipivoxil, Alefacept, ALN-RSV01, AME-133, AMG-317, Aminolevulinic acid methyl ester, Amlodipine besylate/atorvastatin calcium, Anisodamine, Anti-IL-5 receptor antibody, Apremilast, Aripiprazole, Atacicept, Atazanavir sulfate, Atrasentan; Banoxantrone, Bevacizumab, BIBW-2992, Binodenoson, BMS-387032; cAC10, Caldaret hydrate, CD-NP, Ceftobiprole medocaril, Celivarone fumarate, Certolizumab pegol, Cholesteryl hydrophobized polysaccharide-Her2 protein complex, Choline fenofibrate, Cilengitide, Cinaciguat, Curcumin, Custirsen sodium, Cypher, CYT-6091; Dalcetrapib, Deforolimus, Desvenlafaxine succinate, DHA-paclitaxel, DP6-001; E-7010, E75, Ecogramostim, EGF-P64K, EnvPro, Enzastaurin hydrochloride, Escitalopram oxalate, Ezetimibe, Ezetimibe/simvastatin; Fenretinide; Gefitinib, Golimumab, Green tea catechins, GTI-2040, GW-406381; HPV16 E6 E7, HPV-16/18 AS04, HPV-6/11/16/18; ICC-1132, Immune globulin intravenous (human), Indacaterol, Intranasal insulin; Kahalalide F; Lactobacillus rhamnosus, Laromustine, Laropiprant, GTI-2040; MAb 3H1, Mepolizumab, Mifamurtide, Milataxel, MP4; Nebicapone, Nelarabine, Neuradiab; Oncolytic HSV; PCV7, PHX-1149, Pimecrolimus, Pralatrexate, Pramiconazole; Ranibizumab, Reolysin, Rilonacept, Rolofylline, Romidepsin; S-32865, Shigella dysenteriae 1 vaccine; Taranabant, Taxus, TZP-101; Ustekinumab; Vitespen; Zileuton, Zycure.
20530710 4 The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents.

References
In this table a number of abstracts for BIBW2992 are shown. The abstracts were obtained from the database based on the number of hits with BIBW2992 or one of its synonyms. The search button in the top right can be used to only show abstracts with a particular additional keyword.

References
BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors. Natalie Minkovsky;Alan Berezov. 2008. Curr Opin Investig Drugs. 9. PMID: 19037840

The anilino-quinazoline derivative BIBW-2992, which is being developed by Boehringer Ingelheim Corp for the potential treatment of solid tumors, is an oral dual receptor tyrosine kinase inhibitor of human EGF receptor (EGFR) and human epidermal growth factor receptor-2 (HER-2)/neu. EGFR and HER-2/neu activate numerous signaling pathways leading to cancer cell proliferation, survival and migration. In vitro, BIBW-2992 effectively and selectively inhibited EGFR and HER-2/neu and inhibited EGFR and HER-2/neu total tyrosine phosphorylation and tumor cell proliferation in vivo. Importantly, BIBW-2992 was active against tumors overexpressing EGFR with the secondary Thr790Met point mutation, which confers resistance to the first-generation EGFR inhibitors gefitinib and erlotinib. In phase I/II trials, BIBW-2992 was effective in patients with solid tumors, including those with NSCLC tumors activating mutations in the EGFR tyrosine kinase domain. BIBW-2992 was generally well tolerated with the main adverse effects being gastrointestinal or cutaneous disorders. At the time of publication, BIBW-2992 was undergoing phase II trials for NSCLC, breast and prostate cancers, head and neck carcinoma, as well as glioma. BIBW-2992 was granted Fast-Track status by the FDA for NSCLC and was investigated in phase III trials for this indication.
Enhanced anticancer effect of the combination of BIBW2992 and thymidylate synthase-targeted agents in non-small cell lung cancer with the T790M mutation of epidermal growth factor receptor. Ken Takezawa;Isamu Okamoto;Junko Tanizaki;Kiyoko Kuwata;Haruka Yamaguchi;Masahiro Fukuoka;Kazuto Nishio;Kazuhiko Nakagawa. 2010. Mol Cancer Ther. 9. PMID: 20530710

Most non-small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET. We have now investigated the effects of combination treatment with thymidylate synthase (TS)-targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation. The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo. The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents. BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance in NSCLC with the T790M mutation of EGFR.
HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy. Samanthi A Perera;Danan Li;Takeshi Shimamura;Maria G Raso;Hongbin Ji;Liang Chen;Christa L Borgman;Sara Zaghlul;Kathleyn A Brandstetter;Shigeto Kubo;Masaya Takahashi;Lucian R Chirieac;Robert F Padera;Roderick T Bronson;Geoffrey I Shapiro;Heidi Greulich;Matthew Meyerson;Ulrich Guertler;Pilar Garin Chesa;Flavio Solca;Ignacio I Wistuba;Kwok-Kin Wong. 2009. Proc Natl Acad Sci U S A. 106. PMID: 19122144

Mutations in the HER2 kinase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2(YVMA)) in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2(YVMA) is essential for tumor maintenance, suggesting a key role for HER2 in lung adenosquamous tumorigenesis. Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2(YVMA) transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage. Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways. Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.
Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation. Geping Qu;Changting Liu;Baojun Sun;Changxi Zhou;Zhijian Zhang;Peng Wang. 2014. Oncol Rep. 32. PMID: 24842595

Although the EGFR tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown marked effects against EGFR-mutated lung cancer, patients acquire resistance by various mechanisms, including the EGFR T790M mutation and Met induction, consequently suffering relapse. Thus, novel agents to overcome EGFR-TKI resistance are urgently needed. We aimed to investigate the inhibitory effects of a combination of BIBW2992 (irreversible EGFR inhibitor)/ARQ 197 (MET inhibitor) on the human lung adenocarcinoma cell line H1975. H1975 cells (harboring a T790M mutation in EGFR) were treated with erlotinib, BIBW2992 or ARQ 197 separately or with combinations of erlotinib/ARQ 197 or BIBW2992/ARQ 197. Cell growth, apoptosis and cell cycle distribution were evaluated by MTT assay, Annexin V/propidium iodide (PI) double staining and flow cytometry, respectively. EGFR, MET, AKT, ERK and the respective phosphorylated counterparts were detected by western blot analysis. Pathway-specific knockdown of MET and/or EGFR kinase signaling was achieved by siRNA interference. H1975 cells displayed EGFR and MET activation, and were resistant to erlotinib. The BIBW2992/ARQ 197 combination significantly inhibited growth, induced cell cycle arrest and apoptosis, and altered the phosphorylation of EGFR, MET, AKT and ERK1/2 in the H1975 cells. Phosphorylation of AKT and ERK1/2, downstream effectors of the EGFR and MET pathways, was not affected by the other tested treatments. Finally, knockdown of MET and/or EGFR in the H1975 cells confirmed the enhanced downstream inhibition of both MET and EGFR pathways. Combination of an irreversible EGFR inhibitor and MET inhibitor is effective in controlling H1975 cells with acquired resistance to erlotinib, by a mechanism involving the downregulation of PI3K/AKT and MEK/ERK signaling pathways.
The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFR T790M-mutated lung cancer. Tae-Gul Lee;Eun-Hui Jeong;Seo Yun Kim;Hye-Ryoun Kim;Cheol Hyeon Kim. 2014. Int J Cancer. 136. PMID: 25382705

To overcome T790M-mediated acquired resistance of lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), second generation TKIs such as BIBW2992 (afatinib) and third generation TKIs including WZ4002 have been developed. However, clinical data on their efficacy in treating T790M mutant tumors are lacking. Histone deacetylase (HDAC) inhibitors have been reported to arrest cell growth and to lead to differentiation and apoptosis of various cancer cells, both in vitro and in vivo. In the present study, we assessed whether the combination of suberoylanilide hydroxamic acid (SAHA, vorinostat), a potent HDAC inhibitor, and BIBW2992 or WZ4002 could overcome EGFR TKI resistance associated with T790M mutation in lung cancer cells. While treatment with BIBW2992 or WZ4002 alone slightly reduced the viability of PC-9G and H1975 cells, which possess T790M mutation, combining them with SAHA resulted in significantly decreased cell viability through the activation of the apoptotic pathway. This combination also enhanced autophagy occurrence and inhibition of autophagy significantly reduced the apoptosis induced by the combination treatment, showing that autophagy is required for the enhanced apoptosis. Caspase-independent autophagic cell death was also induced by the combination treatment with SAHA and either BIBW2992 or WZ4002. Finally, the combined treatment with SAHA and either BIBW2992 or WZ4002 showed an enhanced anti-tumor effect on xenografts of H1975 cells in vivo. In conclusion, the combination of new generation EGFR TKIs and SAHA may be a new strategy to overcome the acquired resistance to EGFR TKIs in T790M mutant lung cancer.
BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. D Li;L Ambrogio;T Shimamura;S Kubo;M Takahashi;L R Chirieac;R F Padera;G I Shapiro;A Baum;F Himmelsbach;W J Rettig;M Meyerson;F Solca;H Greulich;K-K Wong. 2008. Oncogene. 27. PMID: 18408761

Genetic alterations in the kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors. Although first-generation reversible, ATP-competitive inhibitors showed encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR mutations, almost all patients developed resistance to these inhibitors over time. Such resistance to first-generation EGFR inhibitors was frequently linked to an acquired T790M point mutation in the kinase domain of EGFR, or upregulation of signaling pathways downstream of HER3. Overcoming these mechanisms of resistance, as well as primary resistance to reversible EGFR inhibitors driven by a subset of EGFR mutations, will be necessary for development of an effective targeted therapy regimen. Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms. Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.
The dual PI3K/mTOR inhibitor BEZ235 restricts the growth of lung cancer tumors regardless of EGFR status, as a potent accompanist in combined therapeutic regimens. Yi-Ying Wu;Hung-Chang Wu;Jia-En Wu;Kuo-Yen Huang;Shuenn-Chen Yang;Si-Xuan Chen;Chao-Jung Tsao;Keng-Fu Hsu;Yuh-Ling Chen;Tse-Ming Hong. 2019. J Exp Clin Cancer Res. 38. PMID: 31262325

BACKGROUND: Lung cancer is the most common cause of cancer-related mortality worldwide despite diagnostic improvements and the development of targeted therapies, notably including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling has been shown to contribute to tumorigenesis, tumor progression, and resistance to therapy in most human cancer types, including lung cancer. Here, we explored the therapeutic effects of co-inhibition of PI3K and mTOR in non-small-cell lung cancer (NSCLC) cells with different EGFR status. METHODS: The antiproliferative activity of a dual PI3K/mTOR inhibitor BEZ235 was examined by the WST-1 assay and the soft agar colony-formation assay in 2 normal cell lines and 12 NSCLC cell lines: 6 expressing wild-type EGFR and 6 expressing EGFR with activating mutations, including exon 19 deletions, and L858R and T790 M point mutations. The combination indexes of BEZ235 with cisplatin or an EGFR-TKI, BIBW2992 (afatinib), were calculated. The mechanisms triggered by BEZ235 were explored by western blotting analysis. The anti-tumor effect of BEZ235 alone or combined with cisplatin or BIBW2992 were also studied in vivo. RESULTS: BEZ235 suppressed tumor growth in vitro and in vivo by inducing cell-cycle arrest at G1 phase, but without causing cell death. It also reduced the expression of cyclin D1/D3 by regulating both its transcription and protein stability. Moreover, BEZ235 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells by enhancing or prolonging DNA damage and BIBW2992-induced apoptosis in EGFR-TKI-resistant NSCLC cells containing a second TKI-resistant EGFR mutant. CONCLUSIONS: The dual PI3K/mTOR inhibition by BEZ235 is an effective antitumor strategy for enhancing the efficacy of chemotherapy or targeted therapy, even as a monotherapy, to restrict tumor growth in lung cancer treatment.
Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Gregory J Riely. 2008. J Thorac Oncol. 3. PMID: 18520300

Approximately 10 to 15% of patients with non-small cell lung cancer have tumors that depend on activation of the epidermal growth factor receptor (EGFR), as evidenced by mutations in EGFR. In these patients, there is often an initial dramatic response to treatment with the first-generation EGFR tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib. A small number of patients with EGFR mutations have primary resistance to erlotinib and gefitinib, and most patients who initially respond to treatment with erlotinib or gefitinib will develop resistance to first-generation EGFR TKIs. The problems with both primary and acquired resistance to erlotinib and gefitinib support the need for development of additional agents that inhibit EGFR signaling in such patients. This is an overview of three representative second-generation EGFR TKIs. HKI-272, a second-generation irreversible EGFR TKI that also inhibits HER2, has completed accrual of a phase II trial in both untreated patients and patients with acquired resistance to erlotinib or gefitinib. XL647 is a reversible inhibitor of EGFR, HER2, and vascular epidermal growth factor receptor. Preclinical work shows that XL647 can inhibit cell lines bearing mutated forms of EGFR that have been associated with acquired resistance. BIBW2992 is an irreversible EGFR TKI that also inhibits HER2 and vascular epidermal growth factor receptors. In vitro work shows that this compound inhibits wild-type EGFR, EGFR exon 19 deletion, EGFR L858R, and EGFR T790M, the mutation associated with acquired resistance. The preliminary results from phase I and phase II trials for BIBW-2992 and XL647 are discussed.
Epidermal growth factor receptor: is it a feasible target for the treatment of osteosarcoma? Jun Ah Lee;Yunmi Ko;Dong Ho Kim;Jung Sub Lim;Chang-Bae Kong;Wan Hyeong Cho;Dae-Geun Jeon;Soo-Yong Lee;Jae-Soo Koh. 2012. Cancer Res Treat. 44. PMID: 23091447

PURPOSE: Features of epidermal growth factor receptor (EGFR) expression in osteosarcoma and in vitro efficacies of EGFR inhibitors against osteosarcoma cells were evaluated. MATERIALS AND METHODS: Thirty biopsy samples of osteosarcoma patients were retrospectively analyzed for EGFR protein expression by immunohistochemistry. Relationships between EGFR expression and clinicopathologic characteristics and treatment outcomes were evaluated. Four osteosarcoma cell lines were analyzed for EGFR and p-EGFR expression by western blotting. Efficacies of gefitinib and BIBW2992 on osteosarcoma cells were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Tyrosine kinase domains in exons 18 to 21 were sequenced and gene expression analyses of EGFR and PTEN were performed in four osteosarcoma cell lines. RESULTS: EGFR protein was expressed in 27 (90%) samples (6 low, 12 intermediate, 9 high) and in three cell lines. Intermediate or high staining for EGFR was related to a tumor volume<150 mL (p<0.001) and histologic subtype other than osteoblastic type (p=0.03). However, EGFR expression was not associated with histologic response to preoperative chemotherapy or survival. Gefitinib and BIBW 2992 did not have any significant inhibitory effect on cell viabilities. DNA sequencing analysis revealed three osteosarcoma cell lines have single base changes at codon 2361 of exon 20 (G to A), without affecting translation results. Furthermore, no mutation was found to be associated with constitutive EGFR activation. CONCLUSION: In the present study, gefitinib and BIBW2992 were not effective against osteosarcoma cells. However, as osteosarcoma cells express EGFR, further studies are necessary to explore the potential of other therapeutic agents targeting EGFR.
Inhibition of β-Catenin enhances the anticancer effect of irreversible EGFR-TKI in EGFR-mutated non-small-cell lung cancer with a T790M mutation. Yosuke Togashi;Hidetoshi Hayashi;Masato Terashima;Marco A de Velasco;Kazuko Sakai;Yoshihiko Fujita;Shuta Tomida;Kazuhiko Nakagawa;Kazuto Nishio. 2014. J Thorac Oncol. 10. PMID: 25384171

INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) with somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) generally respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). β-Catenin is a key component of the Wnt/β-Catenin signal and is an important oncogene that is involved in the pathogenesis and progression of malignant tumors, especially cancer stem cells. METHODS AND RESULTS: We found that EGFR-mutated NSCLC cell lines exhibited a high expression level of β-Catenin, compared with cell lines with the wild-type EGFR gene, and XAV939 (a β-Catenin inhibitor) enhanced the sensitivities to EGFR-TKI in EGFR-mutated NSCLC cell lines. In EGFR-mutated NSCLC cell lines with the acquired resistance threonine-to-methionine mutation in codon 790 (T790M) mutation, XAV939 enhanced the sensitivity of the cells to an irreversible EGFR-TKI but not a reversible EGFR-TKI. The combination of XAV939 and EGFR-TKIs strongly inhibited the β-Catenin signal and strongly decreased the phosphorylation of EGFR, compared with the use of EGFR-TKIs alone, suggesting an interaction between EGFR and the β-Catenin signal. The stem cell-like properties of the EGFR-mutated cell line carrying the T790M mutation were inhibited by XAV939 and BIBW2992 (an irreversible EGFR-TKI). Furthermore, the stem cell-like properties were strongly inhibited by a combination of both the agents. A xenograft study demonstrated that β-Catenin knockdown enhanced the antitumor effect of BIBW2992 in the EGFR-mutated NSCLC cell line carrying the T790M mutation. CONCLUSION: Our findings indicate that β-Catenin might be a novel therapeutic target in EGFR-mutated NSCLC carrying the T790M mutation.
Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2 (HER2/neu). Alison Reid;Laura Vidal;Heather Shaw;Johann de Bono. 2007. Eur J Cancer. 43. PMID: 17208435

Targeting of epidermal growth factor receptor (EGFR) and HER2 is a proven anti-cancer strategy. However, heterodimerisation, compensatory 'crosstalk' and redundancy exist in the ErbB network, and there is therefore a sound scientific rationale for dual inhibition of EGFR and HER2. Trials of approved agents in combination, for example trastuzumab and cetuximab, are underway. There is also a new generation of small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mABs) that target two or more ErbB receptors. Lapatinib, a TKI of EGFR and HER2, has shown clinical benefit in trastuzumab refractory breast cancer and is poised for FDA approval. Other agents include BIBW-2992 and HKI-272, irreversible TKIs of EGFR and HER2, and pertuzumab, a heterodimerisation inhibitor of EGFR and HER2.
Gateways to clinical trials. M Bayes;X Rabasseda;J R Prous. 2007. Methods Find Exp Clin Pharmacol. 28. PMID: 17235418

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 5-Methyltetrahydrofolate, 9-aminocamptothecin; AdPEDF.11, AE-37, albumin interferon alfa, alicaforsen sodium, alvocidib hydrochloride, AMG-706, arginine butyrate, avanafil, axitinib, azimilide hydrochloride; BAY-579352, belagenpumatucel-L, beta-lapachone, BHT-3009, BIBW-2992, bremelanotide, BX-471; Casopitant mesylate, cediranib, certolizumab pegol, CH-1504, ChimeriVax-West Nile, clofazimine, CpG-7909, curcumin, Cypher; Dapoxetine hydrochloride, darusentan, diflomotecan, D-methionine, dnaJP1, D-serine, DTPw-HB Hib-MenAC, DTPw-HepB-Hib; E-7010, ecogramostim, edodekin alfa, EGFRvlll peptide vaccine, elcometrine, elcometrine/ethinylestradiol, elsilimomab, enrasentan, ertumaxomab, etalocib sodium, exisulind; Fenretinide, fesoterodine, fingolimod hydrochloride, fontolizumab; Gefitinib, gemtuzumab ozogamicin, ghrelin (human), GV-1001; HTU-PA, human papillomavirus vaccine; Indacaterol, indiplon, interleukin-21, intranasal insulin, irinotecan hydrochloride/floxuridine, ISIS-301012, ispinesib mesylate, ixabepilone; K562/GM-CSF; Lapatinib, L-BLP-25, linezolid, liposome encapsulated paclitaxel, LY-2124275; MC-1, MC-1/lisinopril, MDX-066, melanoma vaccine, MMR-V, multivalent (ACYW) meningitis vaccine; Nilotinib, nobori, nociceptin; Oblimersen sodium, orbofiban acetate, ospemifene; Paliperidone, panitumumab, PEG-filgrastim, PEGylated interferon alfacon-1, perflubutane, pertuzumab, phenserine tartrate, phVEGF-A165, pleconaril, prasugrel, prednisolone sodium metasulfobenzoate; R-411, recombinant malaria vaccine, rhGM-CSF, roflumilast, romidepsin, ruboxistaurin mesilate hydrate; Sirolimus-eluting stent, SR-4554, St. John's Wort extract; Talabostat, Taxus, TGN-255, tifacogin, tiotropium bromide, tolevamer sodium, trabectedin, tretinoin LF; Vatalanib succinate; Yellow fever vaccine, YM-155.
Gateways to clinical trials. M Bayés;X Rabasseda;J R Prous. 2007. Methods Find Exp Clin Pharmacol. 29. PMID: 17922073

[111In]-DOTA-cG250, [131I]-Metuximab injection, [177Lu]-DOTA-cG250; Anatumomab mafenatox, AP-12009; BIBW-2992, Biricodar dicitrate; Cediranib, Cilengitide, Clevidipine, CNTO-528, CNTO-95, CP-870893; Disufenton sodium, DNK-333A; Ecallantide, Enzastaurin hydrochloride, Etravirine, Exatecan mesilate; Fingolimod hydrochloride; Human insulin, Hyaluronic acid; Indisulam, Inhaled insulin, Insulin glargine, Ipilimumab, Irofulven, Ispronicline, ITF-282; J591; KAI-9803; L-Arginine hydrochloride, Laropiprant, LY-518674; Matuzumab, MB-7133, Methylnaltrexone bromide, MVA-5T4; Nemifitide ditriflutate; Obatoclax mesylate, Oral insulin; P-276-00, PF-562271, Picolinic acid; Quercetin; R-109339, R-547, Rivaroxaban, Ruboxistaurin mesilate hydrate; Seliciclib; Terameprocol, Tilarginine hydrochloride, Tolvaptan, Uracil; Vincristine.
Gateways to clinical trials. A Tomillero;M A Moral. 2008. Methods Find Exp Clin Pharmacol. 30. PMID: 18597009

(-)-Epigallocatechin gallate, (-)-Gossypol; Ad.hIFN-beta, AF-37702, Agatolimod sodium, Agomelatine, Alvocidib hydrochloride, ARC-1779; Belimumab, BIBW-2992, Binodenoson, Bortezomib, Bosutinib, Brivaracetam; Cediranib, Clevidipine, CNTO-328, CP-751871, Curcumin; Darapladib, Deforolimus, Denosumab, Desvenlafaxine succinate, Dipyridamole/prednisolone, Dronedarone hydrochloride, DTPw-HBV/Hib 2.5; Ecogramostim, Elacytarabine, Eltrombopag, Eprodisate sodium; Farnesylthiosalicylic acid, Febuxostat, Fenretinide, Ferumoxytol, FMP2.1/AS02A, Forodesine hydrochloride, FP-0011; HuLuc-63, Human Fibroblast Growth Factor 1; Idraparinux sodium, Indium 111 (111In) ibritumomab tiuxetan, Interleukin-21, Ipilimumab, ISS-1018, ITF-2357; Lapaquistat acetate, Laropiprant, Liposomal vincristine, LY-518674; Masitinib mesylate, MAXY-G34, MGCD-0103, Midostaurin, Mitumprotimut-T, MK-0343, MLN-1202, MM-093, Motexafin gadolinium; NB-001, NB-002, Niacin/laropiprant; Oblimersen sodium, Ocrelizumab, Omacetaxine mepesuccinate; Panobinostat, Patupilone, PBI-1402, Perifosine, PHA-739358, Plerixafor hydrochloride, Prasugrel; Regadenoson, RHAMM R3 peptide, Rilonacept, Rivaroxaban, Romiplostim; Safinamide mesilate, Salinosporamide A, Selenite sodium, Sotrastaurin; Thrombin alfa, Tipifarnib, TRO-19622; Vatalanib succinate, Vernakalant hydrochloride, VRC-WNVDNA017-00-VP; YM-155, Yttrium 90 (90Y) ibritumomab tiuxetan; Zosuquidar trihydrochloride.
Gateways to clinical trials. A Tomillero;M A Moral. 2008. Methods Find Exp Clin Pharmacol. 30. PMID: 18773127

11D10, 9vPnC-MnCc; Adalimumab, Adefovir dipivoxil, Alefacept, ALN-RSV01, AME-133, AMG-317, Aminolevulinic acid methyl ester, Amlodipine besylate/atorvastatin calcium, Anisodamine, Anti-IL-5 receptor antibody, Apremilast, Aripiprazole, Atacicept, Atazanavir sulfate, Atrasentan; Banoxantrone, Bevacizumab, BIBW-2992, Binodenoson, BMS-387032; cAC10, Caldaret hydrate, CD-NP, Ceftobiprole medocaril, Celivarone fumarate, Certolizumab pegol, Cholesteryl hydrophobized polysaccharide-Her2 protein complex, Choline fenofibrate, Cilengitide, Cinaciguat, Curcumin, Custirsen sodium, Cypher, CYT-6091; Dalcetrapib, Deforolimus, Desvenlafaxine succinate, DHA-paclitaxel, DP6-001; E-7010, E75, Ecogramostim, EGF-P64K, EnvPro, Enzastaurin hydrochloride, Escitalopram oxalate, Ezetimibe, Ezetimibe/simvastatin; Fenretinide; Gefitinib, Golimumab, Green tea catechins, GTI-2040, GW-406381; HPV16 E6 E7, HPV-16/18 AS04, HPV-6/11/16/18; ICC-1132, Immune globulin intravenous (human), Indacaterol, Intranasal insulin; Kahalalide F; Lactobacillus rhamnosus, Laromustine, Laropiprant, GTI-2040; MAb 3H1, Mepolizumab, Mifamurtide, Milataxel, MP4; Nebicapone, Nelarabine, Neuradiab; Oncolytic HSV; PCV7, PHX-1149, Pimecrolimus, Pralatrexate, Pramiconazole; Ranibizumab, Reolysin, Rilonacept, Rolofylline, Romidepsin; S-32865, Shigella dysenteriae 1 vaccine; Taranabant, Taxus, TZP-101; Ustekinumab; Vitespen; Zileuton, Zycure.
Gateways to clinical trials. July-August 2008. A Tomillero;M A Moral. 2008. Methods Find Exp Clin Pharmacol. 30. PMID: 18850047

(-)-Epigallocatechin gallate, 501516, 89-12; Abatacept, Adalimumab, Adefovir dipivoxil, AG-701, Agatolimod sodium, Alefacept, Aliskiren fumarate, Apixaban, Atazanavir sulfate, Atrasentan, Axitinib; BI-1744-CL, BIBF-1120, BIBW-2992, Bortezomib; Carboxyamidotriazole, Caspofungin acetate, CBP-501, Cediranib, Ceftobiprole, Certolizumab pegol, Cetuximab, Cholesteryl hydrophobized polysaccharide-Her2 protein complex, CHP-NY-ESO-1, Cypher; Dalbavancin, Dalcetrapib, Daptomycin, Darapladib, Deferasirox, Deforolimus, Denosumab, DNA-HIV-C, Dovitinib, DR-5001, Dronedarone hydrochloride, DT388IL3; E75, EC-17/EC-90, Ecogramostim, Efungumab, Entecavir, EP HIV-1090, EP-2101, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Faropenem daloxate, Fluticasone furoate, Fondaparinux sodium, Fospropofol disodium, Fulvestrant; Golimumab, GSK-089, GW-590735; HO/03/03, hTERT572, hTERT572Y; Iloperidone; Immunoglobulin intravenous (human), Ispinesib mesylate, Istradefylline, Ixabepilone; JR-031, JX-594; KLH; Laropiprant, Lecozotan hydrochloride, Lenalidomide, Lestaurtinib, Linezolid; MGCD-0103, MK-0646, MVA-BN Measles; NI-0401, Niacin/laropiprant, NSC-719239, NYVAC-C; Ospemifene; Paliperidone palmitate, PAN-811, PCV7, Pegfilgrastim, Peginterferon alfa-2a, PEGirinotecan, Perifosine, Pertuzumab, PF-00299804, Picoplatin, Pimavanserin tartrate, Pitavastatin calcium, Pomalidomide, Prasterone, Pratosartan, Prucalopride, PSMA27/pDOM, Pyridoxal phosphate; QS-21, Quercetin; Rebimastat, Rimonabant, Rolofylline, Romidepsin, Rosuvastatin calcium, RTS,S/SBAS2; SCH-530348, SN-29244, Soblidotin, Sodium dichloroacetate, Solifenacin succinate, Sorafenib, Spheramine, SU-6668, Succinobucol; Taranabant, Taxus, Telaprevir, Telavancin hydrochloride, Telbivudine, Tenofovir disoproxil fumarate, Tigecycline, Tiotropium bromide, Tocilizumab, Triphendiol; UC-781, Udenafil, UNIL-025; V-5 Immunitor, Valsartan/amlodipine besylate, Varenicline tartrate, Velafermin, Vernakalant hydrochloride, Vinflunine, Vitespen, Vorinostat, VX-001; Xience V, XRP-0038; Yttrium Y90 Epratuzumab; Z-360, Ziconotide, Ziprasidone hydrochloride, Zotarolimus, Zotarolimus-eluting stent.
Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. Lucia Regales;Yixuan Gong;Ronglai Shen;Elisa de Stanchina;Igor Vivanco;Aviva Goel;Jason A Koutcher;Maria Spassova;Ouathek Ouerfelli;Ingo K Mellinghoff;Maureen F Zakowski;Katerina A Politi;William Pao. 2009. J Clin Invest. 119. PMID: 19759520

EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents is the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses in individuals with lung adenocarcinomas characterized by mutations in exons encoding the EGFR tyrosine kinase domain, but disease progression invariably occurs. A major reason for such acquired resistance is the outgrowth of tumor cells with additional TKI-resistant EGFR mutations. Here we used relevant transgenic mouse lung tumor models to evaluate strategies to overcome the most common EGFR TKI resistance mutation, T790M. We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab. Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance. Moreover, this approach could serve as an important model for targeting other receptor tyrosine kinases activated in human cancers.
Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Martin L Sos;Haridas B Rode;Stefanie Heynck;Martin Peifer;Florian Fischer;Sabine Klüter;Vijaykumar G Pawar;Cecile Reuter;Johannes M Heuckmann;Jonathan Weiss;Lars Ruddigkeit;Matthias Rabiller;Mirjam Koker;Jeffrey R Simard;Matthäus Getlik;Yuki Yuza;Tzu-Hsiu Chen;Heidi Greulich;Roman K Thomas;Daniel Rauh. 2010. Cancer Res. 70. PMID: 20103621

Reversible epidermal growth factor receptor (EGFR) inhibitors are the first class of small molecules to improve progression-free survival of patients with EGFR-mutated lung cancers. Second-generation EGFR inhibitors introduced to overcome acquired resistance by the T790M resistance mutation of EGFR have thus far shown limited clinical activity in patients with T790M-mutant tumors. In this study, we systematically analyzed the determinants of the activity and selectivity of the second-generation EGFR inhibitors. A focused library of irreversible as well as structurally corresponding reversible EGFR-inhibitors was synthesized for chemogenomic profiling involving over 79 genetically defined NSCLC and 19 EGFR-dependent cell lines. Overall, our results show that the growth-inhibitory potency of all irreversible inhibitors against the EGFR(T790M) resistance mutation was limited by reduced target inhibition, linked to decreased binding velocity to the mutant kinase. Combined treatment of T790M-mutant tumor cells with BIBW-2992 and the phosphoinositide-3-kinase/mammalian target of rapamycin inhibitor PI-103 led to synergistic induction of apoptosis. Our findings offer a mechanistic explanation for the limited efficacy of irreversible EGFR inhibitors in EGFR(T790M) gatekeeper-mutant tumors, and they prompt combination treatment strategies involving inhibitors that target signaling downstream of the EGFR.
Gateways to clinical trials. A Tomillero;M A Moral. 2010. Methods Find Exp Clin Pharmacol. 31. PMID: 20140276

[Methoxy-(11)C]PD-153035, 2-Methoxyestradiol; Adalimumab, Adecatumumab, Adefovir dipivoxil, ADH-1, ADX-10059, Aflibercept, AIR-human growth hormone, Aliskiren fumarate, AMG-221, Amlodipine besylate/olmesartan medoxomil, Aprepitant; Bavituximab, Bevacizumab, Bexarotene, BIBW-2992, BMS-690514, Bortezomib, Bosentan, Briakinumab; Capecitabine, Certolizumab pegol, Cetuximab, Cholecalciferol, Choline fenofibrate, Chorionic gonadotropin (human), Cixutumumab, Clopidogrel, CP-690550 citrate; Dabigatran, Dacetuzumab, Daclizumab, Dapagliflozin, Darbepoetin alfa, Dasatinib, Denosumab; Efavirenz, Elisidepsin, Enoxaparin, Enzastaurin hydrochloride, Eribulin mesilate, Erlotinib hydrochloride, Everolimus, Exenatide; Fenobam, Figitumumab, Filibuvir, Fondaparinux sodium, Fresolimumab; Gefitinib, Golimumab, Golnerminogene pradenovec; Ifosfamide, Imatinib mesylate, Ipilimumab, Ivabradine hydrochloride, Ixabepilone; Lapatinib ditosylate, Lenalidomide, Levocetirizine dihydrochloride, Liposomal vincristine, Liraglutide; M-118, Masitinib mesylate, Metformin hydrochloride, Micafungin sodium, Moxifloxacin hydrochloride; Neratinib; Oblimersen sodium, Ofatumumab, Olmesartan medoxomil; Paclitaxel nanoparticles, Palifosfamide lysine, Panobacumab, Panobinostat, Patupilone, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Piclozotan hydrochloride hydrate, Pixantrone maleate, Prasterone, Prasugrel, Prednisone, Progesterone, Prucalopride, pVGI.1 (VEGF-2); Retigabine, rhFSH, Rituximab, Rivaroxaban, Rosuvastatin calcium; Salinosporamide A, Selumetinib, Sipuleucel-T, Somatropin, Sorafenib, SSR-244738, Sunitinib malate; Tamoxifen citrate, Teduglutide, Telavancin hydrochloride, Telmisartan, Telmisartan/amlodipine, Telmisartan/hydrochlorothiazide, Temsirolimus, Tenofovir disoproxil fumarate, Tipifarnib, Tolvaptan, Trastuzumab, Trastuzumab-MCC-DM1, Travoprost, Tremelimumab; Valsartan/amlodipine besylate, Valsartan/amlodipine besylate/hydrochlorothiazide, Valsartan/hydrochlorothiazide, Vandetanib, Vorinostat.
Gateways to clinical trials. A Tomillero;M A Moral. 2010. Methods Find Exp Clin Pharmacol. 32. PMID: 20508873

O(6)-Benzylguanine; (-)-Gossypol; Abatacept, AC-2592, Adalimumab, AIDSVAX gp120 B/E, Alemtuzumab, Aliskiren fumarate, ALVAC E120TMG, Ambrisentan, Amlodipine, Anakinra, Aripiprazole, Armodafinil, Atomoxetine hydrochloride, Avotermin; Bevacizumab, BIBW-2992, Bortezomib, Bosentan, Botulinum toxin type B; Canakinumab, CAT-354, Ciclesonide, CMV gB vaccine, Corifollitropin alfa, Daptomycin, Darbepoetin alfa, Dasatinib, Denosumab; EndoTAG-1, Eplerenone, Esomeprazole sodium, Eszopiclone, Etoricoxib, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; F-50040, Fesoterodine fumavate, Fondaparinux sodium, Fulvestrant; Gabapentin enacarbil, Golimumab; Imatinib mesylate, Inhalable human insulin, Insulin glargine, Ivabradine hydrochloride; Lercanidipine hydrochloride/enalapril maleate, Levosimendan, Liposomal vincristine sulfate, Liraglutide; MDV-3100, Mometasone furoate/formoterol fumavate, Multiepitope CTL peptide vaccine, Mycophenolic acid sodium salt, Nabiximols, Natalizumab, Nesiritide; Obeticholic acid, Olmesartan medoxomil, Omalizumab, Omecamtiv mecarbil; Paclitaxel-eluting stent, Paliperidone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, Polymyxin B nonapeptide, PORxin-302, Prasugrel, Pregabalin, Pridopidine; Ranelic acid distrontium salt, Rasagiline mesilate, rDEN4delta30-4995, Recombinant human relaxin H2, rhFSH, Rilonacept, Rolofylline, Rosiglitazone maleate/metformin hydrochloride, Rosuvastatin calcium, Rotigotine; Salcaprozic acid sodium salt, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, Sitaxentan sodium, Sorafenib, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, Temsirolimus, Tenofovir, Tenofovir disoproxil fumarate, Teriparatide, Tiotropium bromide, Tocilizumab, Tolvaptan, Tozasertib, Treprostinil sodium; Ustekinumab; Vardenafil hydrochloride hydrate, Varenicline tartrate, Vatalanib succinate, Voriconazole, Vorinostat; Zotarolimus-eluting stent.
Predictive molecular markers of response to epidermal growth factor receptor(EGFR) family-targeted therapies. Sarah Barton;Naureen Starling;Charles Swanton. 2010. Curr Cancer Drug Targets. 10. PMID: 20718710

Constitutive activation of the EGFR/RAS/PI3K cell-signaling pathway that may occur through molecular aberrations in core pathway components occurs in many solid tumours, including colorectal cancer(CRC), non-small-cell lung cancer(NSCLC) and breast cancer. Predictive biomarkers of response to therapeutics targeting this pathway are necessary to select patients more likely to respond, and importantly, to avoid treating patients likely to suffer a worse outcome with therapy compared to standard of care. Determination of EGFR by immunohistochemistry(IHC) is not strongly predictive of response to EGFR-targeted therapy in CRC and NSCLC. EGFR gene mutations in the tyrosine kinase(TK) binding domain are predictive of response to EGFR tyrosine kinase inhibitors(TKIs) in NSCLC, and the acquisition of a point mutation in a gene encoding an amino acid in an adjacent area, T790M, is predictive of resistance. However, novel irreversible EGFR inhibitors such as BIBW-2992 and HKI-272 may retain activity in tumours with T790M mutations. It is well established in CRC that mutations in KRAS are predictive of resistance to EGFR pathway inhibition, and may predict for a poorer outcome with therapy. Other potentially useful biomarkers of resistance to EGFR-targeted therapy in the process of clinical validation include mutations in BRAF, PTEN loss and PI3KCA mutations, nuclear factor-kappa beta(NF-Κβ) pathway activity, and expression of alternative EGFR ligands. Functional genomics elucidation of drug resistance pathways using RNA interference (RNAi) techniques may provide novel therapeutic approaches in disease resistant to EGFR pathway targeting and accelerate predictive biomarker development.
Growth response of human colorectal tumour cell lines to treatment with afatinib (BIBW2992), an irreversible erbB family blocker, and its association with expression of HER family members. Said Abdullah Khelwatty;Sharadah Essapen;Alan M Seddon;Helmout Modjtahedi. 2011. Int J Oncol. 39. PMID: 21617858

Despite the approval of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs), cetuximab and panitumumab, for the treatment of colorectal cancer patients, there is currently no reliable predictive marker for response to therapy. In addition, the duration of response is often limited. Therefore, this study aimed to investigate the effect of afatinib, an irreversible erbB family blocker, as a single agent or in combination with cytotoxic drugs (5-fluorouracil, irinotecan and oxaliplatin) or mAb ICR62 on the proliferation of a panel of human colorectal tumour cell lines and the association between the expression levels of the EGFR family members and response to treatment. Of the cells examined, EGFR-overexpressing DiFi cells were the most sensitive to treatment with both afatinib (IC50=45 nM) and ICR62 (IC50=4.33 nM). Afatinib also inhibited the growth of other tumour cell lines with IC50 values which ranged from 0.33 µM (CCL-221) to 1.62 µM (HCT-116). A significant association was found between the co-expression of EGFR, human epidermal growth factor receptor (HER)-2 and HER-3 and response to treatment with afatinib (R=0.915, P=0.021). Treat-ment with afatinib and cytotoxic drugs was accompanied by an increase in the proportion of these cells in the sub-G0/G1 and in the S and G2/M phase of the cell cycle, respectively. We conclude that afatinib as monotherapy or in combination with other drugs shows activity in colorectal tumour cells and that determination of the co-expression of HER family members should be conducted in clinical trials using drugs targeting erbB signaling. This approach could lead to the identification of a specific subpopulation of cancer patients more likely to benefit from erbB-directed therapy.
Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models. Mi Young Cha;Kwang-Ok Lee;Mira Kim;Ji Yeon Song;Kyu Hang Lee;Jongmin Park;Yun Jung Chae;Young Hoon Kim;Kwee Hyun Suh;Gwan Sun Lee;Seung Bum Park;Maeng Sup Kim. 2011. Int J Cancer. 130. PMID: 21732342

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases has been implicated in a variety of cancers. In particular, activating mutations such as the L858R point mutation in exon 21 and the small in-frame deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients. Clinical treatment of patients is limited by the development of drug resistance resulting mainly from a gatekeeper mutation (T790M). In this study, we evaluated the therapeutic potential of a novel, irreversible pan-HER inhibitor, HM781-36B. The results from this study show that HM781-36B is a potent inhibitor of EGFR in vitro, including the EGFR-acquired resistance mutation (T790M), as well as HER-2 and HER-4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992). HM781-36B treatment of EGFR DelE746_A750-harboring erlotinib-sensitive HCC827 and EGFR L858R/T790M-harboring erlotinib-resistant NCI-H1975 NSCLC cells results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins. Additionally, HM781-36B shows an excellent efficacy in a variety of EGFR- and HER-2-dependent tumor xenograft models, including erlotinib-sensitive HCC827 NSCLC cells, erlotinib-resistant NCI-H1975 NSCLC cells, HER-2 overexpressing Calu-3 NSCLC cells, NCI-N87 gastric cancer cells, SK-Ov3 ovarian cancer cells and EGFR-overexpressing A431 epidermoid carcinoma cancer cells. On the basis of these preclinical results, HM781-36B is the most potent pan-HER inhibitor, which will be advantageous for the treatment of patients with NSCLC including clinical limitation caused by acquired mutation (EGFR T790M), breast cancer and gastric cancer.
Dual kinase inhibition of EGFR and HER2 overcomes resistance to cetuximab in a novel in vivo model of acquired cetuximab resistance. Kelly M Quesnelle;Jennifer R Grandis. 2011. Clin Cancer Res. 17. PMID: 21791633

PURPOSE: Acquired resistance to cetuximab, a chimeric epidermal growth factor receptor (EGFR)-targeting monoclonal antibody, is a widespread problem in the treatment of solid tumors. The paucity of preclinical models has limited investigations to determine the mechanism of acquired therapeutic resistance, thereby limiting the development of effective treatments. The purpose of this study was to generate cetuximab-resistant tumors in vivo to characterize mechanisms of acquired resistance. EXPERIMENTAL DESIGN: We generated cetuximab-resistant clones from a cetuximab-sensitive bladder cancer cell line in vivo by exposing cetuximab-sensitive xenografts to increasing concentrations of cetuximab, followed by validation of the resistant phenotype in vivo and in vitro using invasion assays. A candidate-based approach was used to examine the role of HER2 on mediating cetuximab resistance both in vitro and in vivo. RESULTS: We generated a novel model of cetuximab resistance, and, for the first time in the context of EGFR-inhibitor resistance, we identified increased phosphorylation of a C-terminal fragment of HER2 (611-CTF) in cetuximab-resistant cells. Afatinib (BIBW-2992), an irreversible kinase inhibitor targeting EGFR and HER2, successfully inhibited growth of the cetuximab-resistant cells in vitro. When afatinib was combined with cetuximab in vivo, we observed an additive growth inhibitory effect in cetuximab-resistant xenografts. CONCLUSIONS: These data suggest that the use of dual EGFR-HER2 kinase inhibitors can enhance responses to cetuximab, perhaps in part due to downregulation of 611-CTF. This study conducted in a novel in vivo model provides a mechanistic rationale for ongoing phase I clinical trials using this combination treatment modality.
Evaluation of the antitumor effects and mechanisms of PF00299804, a pan-HER inhibitor, alone or in combination with chemotherapy or targeted agents in gastric cancer. Hyun-Jin Nam;Keith A Ching;Julie Kan;Hwang-Phill Kim;Sae-Won Han;Seock-Ah Im;Tae-You Kim;James G Christensen;Do-Youn Oh;Yung-Jue Bang. 2011. Mol Cancer Ther. 11. PMID: 22135232

Recently, HER2-directed treatment, such as trastuzumab, has shown clinical benefit in HER2-amplified gastric cancer. On the basis of recent studies about epidermal growth factor receptor (EGFR) or HER2-targeting agents (including gefitinib, lapatinib, and trastuzumab) in gastric cancer, the potent effects of pan-HER inhibitors targeting the HER family are anticipated. In this study, we evaluated the activity and mechanisms of PF00299804, an irreversible pan-HER inhibitor, in gastric cancer in vitro and in vivo models. PF00299804 showed significant growth-inhibitory effects in HER2-amplified gastric cancer cells (SNU216, N87), and it had lower 50% inhibitory concentration values compared with other EGFR tyrosine kinase inhibitors, including gefitinib, lapatinib, BIBW-2992, and CI-1033. PF00299804 induced apoptosis and G(1) arrest and inhibited phosphorylation of receptors in the HER family and downstream signaling pathways including STAT3, AKT, and extracellular signal-regulated kinases (ERK) in HER2-amplified gastric cancer cells. PF00299804 also blocked EGFR/HER2, HER2/HER3, and HER3/HER4 heterodimer formation as well as the association of HER3 with p85α in SNU216 cells. The combination of PF00299804 with clinically relevant chemotherapeutic agents or molecular-targeted agents including trastuzumab (an anti-HER2 monoclonal antibody), CP751871 (an IGF1R inhibitor), PD0325901 (an ERK1/2 inhibitor), and PF04691502 (a PI3K/mTOR inhibitor) produced synergistic effects. These findings indicate that PF00299804 can be used as a targeted therapy for the treatment of HER2-amplified gastric cancer through inhibition of HER family heterodimer formation and may augment antitumor efficacy of chemotherapeutic and/or molecular-targeted agents.
New therapies in HER2-positive breast cancer: a major step towards a cure of the disease? Ahmad Awada;Ivana Bozovic-Spasojevic;Louis Chow. 2012. Cancer Treat Rev. 38. PMID: 22305205

Overexpression of the human epidermal growth factor receptor 2 (HER2) predicts a poor prognosis in metastatic breast cancer. While the introduction of HER2-targeted therapies, such as the monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib, has significantly improved outcomes in HER2+ breast cancer compared with previously available therapies, use of these targeted therapies is often limited by the development of drug resistance and tolerability issues. These limitations create the need for further development and investigation of new targeted therapies that show potent and selective inhibition of these targets or closely connected molecular pathways. Recently, several agents have demonstrated promising activity in HER2+ metastatic breast cancer, either as monotherapy or in combination therapy, including the tyrosine-kinase inhibitors neratinib (HKI-272) and afatinib (BIBW-2992) and the anti-HER2 monoclonal antibodies pertuzumab and trastuzumab-DM1 (T-DM1). Agents that target other molecular pathways, such as the vascular endothelial growth factor receptor, mammalian target of rapamycin, PI3-kinases, insulin-like growth factor (IGFR), HSP-90, and other kinases also have potential, in combination with anti-HER2 and/or other systemic therapies, to be active in this subtype of breast cancer. Innovative clinical studies are required in well-characterized patient populations to define the true clinical value of these emerging new approaches.
Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer. Wei Wang;Qi Li;Shinji Takeuchi;Tadaaki Yamada;Hitomi Koizumi;Takahiro Nakamura;Kunio Matsumoto;Naofumi Mukaida;Yasuhiko Nishioka;Saburo Sone;Takayuki Nakagawa;Toshimitsu Uenaka;Seiji Yano. 2012. Clin Cancer Res. 18. PMID: 22317763

PURPOSE: Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI-resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs. EXPERIMENTAL DESIGN: The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into severe combined immunodeficient mice, and the therapeutic effects of E7050 plus gefitinib were assayed. RESULTS: E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells. CONCLUSIONS: A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.
Loss of activating EGFR mutant gene contributes to acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells. Keisuke Tabara;Rina Kanda;Kahori Sonoda;Takuya Kubo;Yuichi Murakami;Akihiko Kawahara;Koichi Azuma;Hideyuki Abe;Masayoshi Kage;Aki Yoshinaga;Tomoko Tahira;Kenshi Hayashi;Tokuzo Arao;Kazuto Nishio;Rafael Rosell;Michihiko Kuwano;Mayumi Ono. 2012. PLoS One. 7. PMID: 22815900

Non-small-cell lung cancer harboring epidermal growth factor receptor (EGFR) mutations attains a meaningful response to EGFR-tyrosine kinase inhibitors (TKIs). However, acquired resistance to EGFR-TKIs could affect long-term outcome in almost all patients. To identify the potential mechanisms of resistance, we established cell lines resistant to EGFR-TKIs from the human lung cancer cell lines PC9 and11-18, which harbored activating EGFR mutations. One erlotinib-resistant cell line from PC9 and two erlotinib-resistant cell lines and two gefitinib-resistant cell lines from 11-18 were independently established. Almost complete loss of mutant delE746-A750 EGFR gene was observed in the erlotinib-resistant cells isolated from PC9, and partial loss of the mutant L858R EGFR gene copy was specifically observed in the erlotinib- and gefitinib-resistant cells from 11-18. However, constitutive activation of EGFR downstream signaling, PI3K/Akt, was observed even after loss of the mutated EGFR gene in all resistant cell lines even in the presence of the drug. In the erlotinib-resistant cells from PC9, constitutive PI3K/Akt activation was effectively inhibited by lapatinib (a dual TKI of EGFR and HER2) or BIBW2992 (pan-TKI of EGFR family proteins). Furthermore, erlotinib with either HER2 or HER3 knockdown by their cognate siRNAs also inhibited PI3K/Akt activation. Transfection of activating mutant EGFR complementary DNA restored drug sensitivity in the erlotinib-resistant cell line. Our study indicates that loss of addiction to mutant EGFR resulted in gain of addiction to both HER2/HER3 and PI3K/Akt signaling to acquire EGFR-TKI resistance.
Glycolysis inhibition sensitizes non-small cell lung cancer with T790M mutation to irreversible EGFR inhibitors via translational suppression of Mcl-1 by AMPK activation. Sun Mi Kim;Mi Ran Yun;Yun Kyoung Hong;Flavio Solca;Joo-Hang Kim;Hyun-Jung Kim;Byoung Chul Cho. 2013. Mol Cancer Ther. 12. PMID: 23883584

The secondary EGF receptor (EGFR) T790M is the most common mechanism of resistance to reversible EGFR-tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations. Although afatinib (BIBW2992), a second-generation irreversible EGFR-TKI, was expected to overcome the acquired resistance, it showed limited efficacy in a recent phase III clinical study. In this study, we found that the inhibition of glycolysis using 2-deoxy-d-glucose (2DG) improves the efficacy of afatinib in H1975 and PC9-GR NSCLC cells with EGFR T790M. Treatment with the combination of 2DG and afatinib induced intracellular ATP depletion in both H1975 and PC9-GR cells, resulting in activation of AMP-activated protein kinase (AMPK). AMPK activation played a central role in the cytotoxicity of the combined treatment with 2DG and afatinib through the inhibition of mTOR. The alteration of the AMPK/mTOR signaling pathway by the inhibition of glucose metabolism induced specific downregulation of Mcl-1, a member of the antiapoptotic Bcl-2 family, through translational control. The enhancement of afatinib sensitivity by 2DG was confirmed in the in vivo PC9-GR xenograft model. In conclusion, this study examined whether the inhibition of glucose metabolism using 2DG enhances sensitivity to afatinib in NSCLC cells with EGFR T790M through the regulation of the AMPK/mTOR/Mcl-1 signaling pathway. These data suggest that the combined use of an inhibitor of glucose metabolism and afatinib is a potential therapeutic strategy for the treatment of patients with acquired resistance to reversible EGFR-TKIs due to secondary EGFR T790M.
Overcoming EGFR T790M-based Tyrosine Kinase Inhibitor Resistance with an Allele-specific DNAzyme. Wei-Yun Lai;Chi-Yuan Chen;Shuenn-Chen Yang;Jer-Yuarn Wu;Cheng-Ju Chang;Pan-Chyr Yang;Konan Peck. 2014. Mol Ther Nucleic Acids. 3. PMID: 24594844

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the main therapeutic agents used to treat non-small-cell lung cancer patients harboring EGFR-activating mutations. However, most of these patients will eventually develop resistance, 50% of which are due to a secondary mutation at T790M in the EGFR. In this paper, we describe the development of an allele-specific DNAzyme, DzT, that can specifically silence EGFR T790M mutant messenger RNA while leaving wild-type EGFR intact. Allele-specific silencing of EGFR T790M expression and downstream signaling by DzT triggered apoptosis in non-small-cell lung cancer cells harboring this mutant. Adding a cholesterol-triethylene glycol group on the 3'-end of DzT (cDzT) improved drug efficacy, increasing inhibitory effect on cell viability from 46 to 79% in T790M/L858R-harboring H1975(TM/LR) non-small-cell lung cancer cells, without loss of allele specificity. Combined treatment with cDzT and BIBW-2992, a second-generation EGFR-tyrosine kinase inhibitor, synergistically inhibited EGFR downstream signaling and suppressed the growth of xenograft tumors derived from H1975(TM/LR) cells. Collectively, these results indicate that the allele-specific DNAzyme, DzT, may provide an alternative treatment for non-small-cell lung cancer that is capable of overcoming EGFR T790M mutant-based tyrosine kinase inhibitor resistance.Molecular Therapy-Nucleic Acids (2014) 3, e150; doi:10.1038/mtna.2014.3; published online 4 March 2014.
Toward precision medicine with next-generation EGFR inhibitors in non-small-cell lung cancer. Timothy A Yap;Sanjay Popat. 2014. Pharmgenomics Pers Med. 7. PMID: 25278773

The use of genomics to discover novel targets and biomarkers has placed the field of oncology at the forefront of precision medicine. First-generation epidermal growth factor receptor (EGFR) inhibitors have transformed the therapeutic landscape of EGFR mutant non-small-cell lung carcinoma through the genetic stratification of tumors from patients with this disease. Somatic EGFR mutations in lung adenocarcinoma are now well established as predictive biomarkers of response and resistance to small-molecule EGFR inhibitors. Despite early patient benefit, primary resistance and subsequent tumor progression to first-generation EGFR inhibitors are seen in 10%-30% of patients with EGFR mutant non-small-cell lung carcinoma. Acquired drug resistance is also inevitable, with patients developing disease progression after only 10-13 months of antitumor therapy. This review details strategies pursued in circumventing T790M-mediated drug resistance to EGFR inhibitors, which is the most common mechanism of acquired resistance, and focuses on the clinical development of second-generation EGFR inhibitors, exemplified by afatinib (BIBW2992). We discuss the rationale, mechanism of action, clinical efficacy, and toxicity profile of afatinib, including the LUX-Lung studies. We also discuss the emergence of third-generation irreversible mutant-selective inhibitors of EGFR and envision the future management of EGFR mutant lung adenocarcinoma.
Exploiting high-throughput cell line drug screening studies to identify candidate therapeutic agents in head and neck cancer. Anthony C Nichols;Morgan Black;John Yoo;Nicole Pinto;Andrew Fernandes;Benjamin Haibe-Kains;Paul C Boutros;John W Barrett. 2014. BMC Pharmacol Toxicol. 15. PMID: 25428177

BACKGROUND: There is an urgent need for better therapeutics in head and neck squamous cell cancer (HNSCC) to improve survival and decrease treatment morbidity. Recent advances in high-throughput drug screening techniques and next-generation sequencing have identified new therapeutic targets in other cancer types, but an HNSCC-specific study has not yet been carried out. We have exploited data from two large-scale cell line projects to clearly describe the mutational and copy number status of HNSCC cell lines and identify candidate drugs with elevated efficacy in HNSCC. METHODS: The genetic landscape of 42 HNSCC cell lines including mutational and copy number data from studies by Garnett et al., and Barretina et al., were analyzed. Data from Garnett et al. was interrogated for relationships between HNSCC cells versus the entire cell line pool using one- and two-way analyses of variance (ANOVAs). As only seven HNSCC cell lines were tested with drugs by Barretina et al., a similar analysis was not carried out. RESULTS: Recurrent mutations in human papillomavirus (HPV)-negative patient tumors were confirmed in HNSCC cell lines, however additional, recurrent, cell line-specific mutations were identified. Four drugs, Bosutinib, Docetaxel, BIBW2992, and Gefitinib, were found via multiple-test corrected ANOVA to have lower IC50 values, suggesting higher drug sensitivity, in HNSCC lines versus non-HNSCC lines. Furthermore, the PI3K inhibitor AZD6482 demonstrated significantly higher activity (as measured by the IC50) in HNSCC cell lines harbouring PIK3CA mutations versus those that did not. CONCLUSION: HNSCC-specific reanalysis of large-scale drug screening studies has identified candidate drugs that may be of therapeutic benefit and provided insights into strategies to target PIK3CA mutant tumors. PIK3CA mutations may represent a predictive biomarker for response to PI3K inhibitors. A large-scale study focused on HNSCC cell lines and including HPV-positive lines is necessary and has the potential to accelerate the development of improved therapeutics for patients suffering with head and neck cancer. This strategy can potentially be used as a template for drug discovery in any cancer type.
Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells. Yongik Lee;Yian Wang;Michael James;Joseph H Jeong;Ming You. 2015. Mol Carcinog. 55. PMID: 26052929

Non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation have benefited from treatment of reversible EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Acquisition of a secondary mutation in EGFR T790M is the most common mechanism of resistance to first generation EGFR TKIs, resulting in therapeutic failure. Afatinib is a second generation of EGFR TKI that showed great efficacy against tumors bearing the EGFR T790M mutation, but it failed to show the improvement on overall survival of lung cancer patients with EGFR mutations possibly because of novel acquired resistance mechanisms. Currently, there are no therapeutic options available for lung cancer patients who develop acquired resistance to afatinib. To identify novel resistance mechanism(s) to afatinib, we developed afatinib resistant cell lines from a parental human-derived NSCLC cell line, H1975, harboring both EGFR L858R and T790M mutations. We found that activation of the insulin-like growth factor 1 receptor (IGF1R) signaling pathway contributes to afatinib resistance in NSCLC cells harboring the T790M mutation. IGF1R knockdown not only significantly sensitizes resistant cells to afatinib, but also induces apoptosis in afatinib resistance cells. In addition, combination treatment with afatinib and linsitinib shows more than additive effects on tumor growth in in vivo H1975 xenograft. Therefore, these finding suggest that IGF1R inhibition or combination of EGFR-IGF1R inhibition strategies would be potential ways to prevent or potentiate the effects of current therapeutic options to lung cancer patients demonstrating resistance to either first or second generation EGFR TKIs.
Preclinical evaluation of afatinib (BIBW2992) in esophageal squamous cell carcinoma (ESCC). Chi Hang Wong;Brigette Buig Yue Ma;Connie Wun Chun Hui;Qian Tao;Anthony Tak Cheung Chan. 2016. Am J Cancer Res. 5. PMID: 26885448

Esophageal squamous cell carcinoma (ESCC) is the eighth most common cancer worldwide. Epidermal growth factor receptors (EGFR) are often overexpressed in esophageal cancers, thus anti-EGFR inhibitors have been evaluated in ESCC. Afatinib was an irreversible inhibitor of these ErbB family receptors. This study characterized the preclinical activity of afatinib in five ESCC cell lines: HKESC-1, HKESC-2, KYSE510, SLMT-1 and EC-1. ESCC cell lines were sensitive to afatinib with IC50 concentrations at lower micro-molar range (at 72 hour incubation: HKESC-1 = 0.002 μM, HKESC-2 = 0.002 μM, KYSE510 = 1.090 μM, SLMT-1 = 1.161 μM and EC-1 = 0.109 μM) with a maximum growth inhibition over 95%. Afatinib can strongly induce G0/G1 cell cycle arrest in HKESC-2 and EC-1 in a dose- and time-dependent manner. The phosphorylation of ErbB family downstream effectors such as pAKT, pS6 and pMAPK were significantly inhibited in HKESC-2 and EC-1. Apoptosis was observed in both cell lines at 24 hours after exposure to afatinib, as determined by the presence of cleaved PARP. Afatinib could effectively inhibit HKESC-2 tumor growth in mice without obvious toxicity. Afatinib alone has shown excellent growth inhibitory effect on ESCC in both in vitro and in vivo models, however, no synergistic effect was observed when it was combined with chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin. In summary, afatinib can inhibit cell proliferation effectively by arresting the cells in G0/G1 phase, as well as inducing apoptosis in ESCC. These findings warrant further studies of afatinib as therapeutic agent in treating ESCC.
Preclinical and clinical studies on afatinib in monotherapy and in combination regimens: Potential impact in colorectal cancer. I De Pauw;A Wouters;J Van den Bossche;M Peeters;P Pauwels;V Deschoolmeester;J B Vermorken;F Lardon. 2016. Pharmacol Ther. 166. PMID: 27373506

Targeting the epidermal growth factor receptor (EGFR) with monoclonal antibodies (mAbs) or tyrosine kinase inhibitors (TKI) has been an interesting therapeutic strategy because aberrant activation of this receptor plays an important role in the tumorgenesis of many cancer types, including colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies, therapeutic resistance is a major clinical problem. In order to overcome resistance to these EGFR-targeted therapies, new treatment options are necessary. In contrast to first generation EGFR inhibitors, afatinib (BIBW2992) is a second-generation irreversible ErbB family blocker that inhibits EGFR as well as HER2 and HER4. Consequently, treatment with afatinib may result in a distinct and more pronounced therapeutic benefit. Preclinical studies have reported promising results for afatinib in monotherapy as well as in combination with other drugs in CRC model systems. Furthermore, clinical studies examining afatinib as single agent and in combination therapy demonstrated manageable safety profile. Nevertheless, only limited antitumor activity has been observed in CRC patients. Although several combination treatments with afatinib have already been investigated, no optimal combination has been identified for CRC patients yet. As molecular tumor characteristics have gained increased importance in the choice of treatment, additional studies with biomarker-driven patient recruitment are required to further explore afatinib efficacy in CRC.
EGF-mediated EGFR/ERK signaling pathway promotes germinative cell proliferation in Echinococcus multilocularis that contributes to larval growth and development. Zhe Cheng;Fan Liu;Xiu Li;Mengya Dai;Jianjian Wu;Xinrui Guo;Huimin Tian;Zhijie Heng;Ying Lu;Xiaoli Chai;Yanhai Wang. 2017. PLoS Negl Trop Dis. 11. PMID: 28241017

BACKGROUND: Larvae of the tapeworm E. multilocularis cause alveolar echinococcosis (AE), one of the most lethal helminthic infections in humans. A population of stem cell-like cells, the germinative cells, is considered to drive the larval growth and development within the host. The molecular mechanisms controlling the behavior of germinative cells are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Using in vitro cultivation systems we show here that the EGFR/ERK signaling in the parasite can promote germinative cell proliferation in response to addition of human EGF, resulting in stimulated growth and development of the metacestode larvae. Inhibition of the signaling by either the EGFR inhibitors CI-1033 and BIBW2992 or the MEK/ERK inhibitor U0126 impairs germinative cell proliferation and larval growth. CONCLUSIONS/SIGNIFICANCE: These data demonstrate the contribution of EGF-mediated EGFR/ERK signaling to the regulation of germinative cells in E. multilocularis, and suggest the EGFR/ERK signaling as a potential therapeutic target for AE and perhaps other human cestodiasis.
Discovering drugs to overcome chemoresistance in ovarian cancers based on the cancer genome atlas tumor transcriptome profile. Fan Wang;Jeremy T-H Chang;Zhenyu Zhang;Gladys Morrison;Aritro Nath;Steven Bhutra;Rong Stephanie Huang. 2018. Oncotarget. 8. PMID: 29383145

Ovarian cancer accounts for the highest mortality among gynecologic cancers, mainly due to intrinsic or acquired chemoresistance. While mechanistic-based methods have been used to identify compounds that can overcome chemoresistance, an effective comprehensive drug screening has yet to be developed. We applied a transcriptome based drug sensitivity prediction method, to the Cancer Genome Atlas (TCGA) ovarian cancer dataset to impute patient tumor response to over 100 different drugs. By stratifying patients based on their predicted response to standard of care (SOC) chemotherapy, we identified drugs that are likely more sensitive in SOC resistant ovarian tumors. Five drugs (ABT-888, BIBW2992, gefitinib, AZD6244 and lenalidomide) exhibit higher efficacy in SOC resistant ovarian tumors when multi-platform of transcriptome profiling methods were employed. Additional in vitro and clinical sample validations were carried out and verified the effectiveness of these agents. Our candidate drugs hold great potential to improve clinical outcome of chemoresistant ovarian cancer.