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REVIEW

Primary and Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer: An Update

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Pages 433-446 | Published online: 10 May 2012

REFERENCES

  • Society AC. Cancer Facts & Figures. American Cancer Society 2012:1–64.
  • Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29.
  • Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.
  • Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–8.
  • Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32.
  • Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448: 561–6.
  • Hirsch FR, Langer CJ. The role of HER2/neu expression and trastuzumab in non-small cell lung cancer. Semin Oncol 2004;31:75–82.
  • Onozato R, Kosaka T, Kuwano H, Sekido Y, Yatabe Y, Mitsudomi T. Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol 2009;4:5–11.
  • Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007;131:1190–203.
  • Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba, II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008;455:1069–75.
  • Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183–232.
  • Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006;7:505–16.
  • Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341–54.
  • Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169–81.
  • Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000;19:6550–65.
  • Kris MG, Natale RB, Herbst RS, Lynch TJ, Jr., Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149–58.
  • Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527–37.
  • Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008;372:1809–18.
  • Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1. J Clin Oncol 2004;22:777–84.
  • Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2. J Clin Oncol 2004;22:785–94.
  • Reck M, Buchholz E, Romer KS, Krutzfeldt K, Gatzemeier U, Manegold C. Gefitinib monotherapy in chemotherapy-naive patients with inoperable stage III/IV non-small-cell lung cancer. Clin Lung Cancer 2006;7:406–11.
  • Takano T, Ohe Y, Sakamoto H, Tsuta K, Matsuno Y, Tateishi U, Yamamoto S, Nokihara H, Yamamoto N, Sekine I, Kunitoh H, Shibata T, Sakiyama T, Yoshida T, Tamura T. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005;23:6829–37.
  • Han S, Kim T, Hwang P, Jeong S, Kim J, Choi I, Oh D, Kim J, Kim D, Chung D, Im S, Kim Y, Lee J, Heo D, Bang Y, Kim N. Predictive and Prognostic Impact of Epidermal Growth Factor Receptor Mutation in Non-Small-Cell Lung Cancer Patients Treated with Gefitinib. J Clin Oncol 2005;23:2493–501.
  • Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–57.
  • Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121–8.
  • Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380–8.
  • Zhang L, Shenglin M, Song X, Han B, Cheng Y, Huang C, Yang S, Liu X, Yun Peng L, Wang M. Efficacy, tolerability, and biomarker analyses from a phase III, randomized, plaebo-controlled, parallel group study of gefitinib as maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2011;29:15s (suppl abstr LBA 7511).
  • Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005;23:5892–9.
  • Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, Milanowski J, Karnicka-Mlodkowski H, Pesek M, Serwatowski P, Ramlau R, Janaskova T, Vansteenkiste J, Strausz J, Manikhas GM, Von Pawel J. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007;25:1545–52.
  • Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, Insa A, Massuti B, Gonzalez-Larriba JL, Paz-Ares L, Bover I, Garcia-Campelo R, Moreno MA, Catot S, Rolfo C, Reguart N, Palmero R, Sanchez JM, Bastus R, Mayo C, Bertran-Alamillo J, Molina MA, Sanchez JJ, Taron M. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958–67.
  • Rosell R, Gervais R, Vergnenegre A, BM, Felip E, Cardenal F, Garcia Gomez R, Pallares C, Sanchez J, Porta R, Cobo M, Di Seri M, Garrido Lopez P, Insa A, De Marinis F, Corre R, Carreras M, Carcereny E, Taron M, LG P-A. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. J Clin Oncol 2011;29:15s (suppl abstr # 7503).
  • Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, Esteban E, Molinier O, Brugger W, Melezinek I, Klingelschmitt G, Klughammer B, Giaccone G. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11:521–9.
  • Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong RP, Baselga J. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 2003;21:2237–46.
  • Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–39.
  • Soh J, Okumura N, Lockwood WW, Yamamoto H, Shigematsu H, Zhang W, Chari R, Shames DS, Tang X, MacAulay C, Varella-Garcia M, Vooder T, Wistuba, II, Lam S, Brekken R, Toyooka S, Minna JD, Lam WL, Gazdar AF. Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. PLoS One 2009;4:e7464.
  • Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–500.
  • Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004;101:13306–11.
  • Bell DW, Lynch TJ, Haserlat SM, Harris PL, Okimoto RA, Brannigan BW, Sgroi DC, Muir B, Riemenschneider MJ, Iacona RB, Krebs AD, Johnson DH, Giaccone G, Herbst RS, Manegold C, Fukuoka M, Kris MG, Baselga J, Ochs JS, Haber DA. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 2005;23:8081–92.
  • Riely GJ, Politi KA, Miller VA, Pao W. Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res 2006;12:7232–41.
  • Jackman DM, Yeap BY, Sequist LV, Lindeman N, Holmes AJ, Joshi VA, Bell DW, Huberman MS, Halmos B, Rabin MS, Haber DA, Lynch TJ, Meyerson M, Johnson BE, Janne PA. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006;12:3908–14.
  • Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, Ince WL, Janne PA, Januario T, Johnson DH, Klein P, Miller VA, Ostland MA, Ramies DA, Sebisanovic D, Stinson JA, Zhang YR, Seshagiri S, Hillan KJ. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23:5900–9.
  • Jang TW, Oak CH, Chang HK, Suo SJ, Jung MH. EGFR and KRAS mutations in patients with adenocarcinoma of the lung. Korean J Intern Med 2009;24:48–54.
  • Reinersman M, Riely G, Nicastri A, Soff G, Getinet A, AG S, Zakowski M, FRusch V, Kris M, Ladanyi M. EGFR and KRAS mutation status of lung adenocarcinomas in African Americans. J Clin Oncol 2009;27.
  • Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher KJ, Settleman J, Haber DA. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 2005;102:7665–70.
  • Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786–92.
  • Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, Chiang A, Yang G, Ouerfelli O, Kris MG, Ladanyi M, Miller VA, Pao W. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006;12:6494–501.
  • Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, Balak M, Chang WC, Yu CJ, Gazdar A, Pass H, Rusch V, Gerald W, Huang SF, Yang PC, Miller V, Ladanyi M, Yang CH, Pao W. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 2007;104:20932–7.
  • Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Janne PA. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039–43.
  • Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.
  • Costa DB, Kobayashi S, Tenen DG, Huberman MS. Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers. Lung Cancer 2007;58:95–103.
  • Greulich H, Chen TH, Feng W, Janne PA, Alvarez JV, Zappaterra M, Bulmer SE, Frank DA, Hahn WC, Sellers WR, Meyerson M. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2005;2:e313.
  • Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008;359:1367–80.
  • Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, Digumarthy S, Muzikansky A, Irimia D, Settleman J, Tompkins RG, Lynch TJ, Toner M, Haber DA. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 2008;359:366–77.
  • Miller V, Zakowski M, Riely G, Pao W, Ladanyi M, Tsao A, Sandler A, Herbst R, Kris M, Johnson H. EGFR mutation and copy number, EGFR protein expression and KRAS mutation as predictors of outcome with Erlotinib in bronchioloalveolar cell carcinoma (BAC): results of a prosepective phase II trial. J Clin Oncol 2006;24.
  • Cappuzzo F, Janne PA, Skokan M, Finocchiaro G, Rossi E, Ligorio C, Zucali PA, Terracciano L, Toschi L, Roncalli M, Destro A, Incarbone M, Alloisio M, Santoro A, Varella-Garcia M. MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann Oncol 2009;20:298–304.
  • Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu N, Zhang T, Marrano P, Whitehead M, Squire JA, Kamel-Reid S, Seymour L, Shepherd FA, Tsao MS. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2008;26:4268–75.
  • Linardou H, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D, Kosmidis P, Papadimitriou CA, Murray S. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008;9:962–72.
  • Suzuki T, Nakagawa T, Endo H, Mitsudomi T, Masuda A, Yatabe Y, Sugiura T, Takahashi T, Hida T. The sensitivity of lung cancer cell lines to the EGFR-selective tyrosine kinase inhibitor ZD1839 (‘Iressa’) is not related to the expression of EGFR or HER-2 or to K-ras gene status. Lung Cancer 2003;42:35–41.
  • Massarelli E, Varella-Garcia M, Tang X, Xavier AC, Ozburn NC, Liu DD, Bekele BN, Herbst RS, Wistuba, II. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res 2007;13:2890–6.
  • Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, Tsurutani J, Dennis PA, Mills GB, Arteaga CL. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 2003;22:2812–22.
  • Tang JM, He QY, Guo RX, Chang XJ. Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer 2006;51:181–91.
  • Lim WT, Zhang WH, Miller CR, Watters JW, Gao F, Viswanathan A, Govindan R, McLeod HL. PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-small cell lung cancer. Oncol Rep 2007;17:853–7.
  • Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA, Lynch T, Johnson BE, Miller VA. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 2010;28:357–60.
  • Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 2008;105:2070–5.
  • Chmielecki J, Foo J, Somwar R, Regales L, Vivanco I, Shen R, Michor F, Pao W. EGFR T790M decreases growth potential of lung tumor cell with drug-sensitivie EGFR mutant alleles in the absence of drug selection. Proc Am Assoc Cancer Res 2009; 1020 abstr# 4217.
  • Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, Pao W, Ladanyi M, Miller VA. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res 2011;17:1616–22.
  • Kumar A, Petri ET, Halmos B, Boggon TJ. Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J Clin Oncol 2008;26:1742–51.
  • Avizienyte E, Ward RA, Garner AP. Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations. Biochem J 2008;415:197–206.
  • Yano S, Wang W, Li Q, Matsumoto K, Sakurama H, Nakamura T, Ogino H, Kakiuchi S, Hanibuchi M, Nishioka Y, Uehara H, Mitsudomi T, Yatabe Y, Sone S. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res 2008;68:9479–87.
  • Munshi N, Jeay S, Li Y, Chen CR, France DS, Ashwell MA, Hill J, Moussa MM, Leggett DS, Li CJ. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther 2010;9:1544–53.
  • Bagai R, Fan W, Ma PC. ARQ-197, an oral small-molecule inhibitor of c-Met for the treatment of solid tumors. IDrugs 2010;13:404–14.
  • Eder JP, Vande Woude GF, Boerner SA, LoRusso PM. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res 2009;15:2207–14.
  • ClinicalTrials.gov. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of ARQ197 Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Subjects with Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer (NSCLC). http://clinicaltrialsgov/ct2/show/NCT01244191 2011.
  • Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S, Rinehart C, Seidel B, Yee D, Arteaga CL, Engelman JA. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 2008;118:2609–19.
  • Shimamura T, Ji H, Minami Y, Thomas RK, Lowell AM, Shah K, Greulich H, Glatt KA, Meyerson M, Shapiro GI, Wong KK. Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272. Cancer Res 2006;66:6487–91.
  • Yano S, T Y, S T, Tachibana K, Minami Y, Noguchi M, Hirsch F. Hepatocyte growth factor expression in EGFR-mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort. J Clin Oncol 2011;29:15s (suppl abstr 7531).
  • Engelman JA, Janne PA, Mermel C, Pearlberg J, Mukohara T, Fleet C, Cichowski K, Johnson BE, Cantley LC. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA 2005;102:3788–93.
  • Coldren CD, Helfrich BA, Witta SE, Sugita M, Lapadat R, Zeng C, Baron A, Franklin WA, Hirsch FR, Geraci MW, Bunn PA, Jr. Baseline gene expression predicts sensitivity to gefitinib in non-small cell lung cancer cell lines. Mol Cancer Res 2006;4:521–8.
  • Frederick BA, Helfrich BA, Coldren CD, Zheng D, Chan D, Bunn PA, Jr., Raben D. Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol Cancer Ther 2007;6:1683–91.
  • Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003;15:740–6.
  • Grunert S, Jechlinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 2003;4:657–65.
  • Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002;2:442–54.
  • Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, Iwata KK, Gibson N, Haley JD. Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 2005;65:9455–62.
  • Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 2005;24:5764–74.
  • Shan B, Yao TP, Nguyen HT, Zhuo Y, Levy DR, Klingsberg RC, Tao H, Palmer ML, Holder KN, Lasky JA. Requirement of HDAC6 for transforming growth factor-beta1-induced epithelial-mesenchymal transition. J Biol Chem 2008;283:21065–73.
  • Witta SE, Gemmill RM, Hirsch FR, Coldren CD, Hedman K, Ravdel L, Helfrich B, Dziadziuszko R, Chan DC, Sugita M, Chan Z, Baron A, Franklin W, Drabkin HA, Girard L, Gazdar AF, Minna JD, Bunn PA, Jr. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res 2006;66:944–50.
  • Witta SE, Dziadziuszko R, Yoshida K, Hedman K, Varella-Garcia M, Bunn PA, Jr., Hirsch FR. ErbB-3 expression is associated with E-cadherin and their coexpression restores response to gefitinib in non-small-cell lung cancer (NSCLC). Ann Oncol 2009;20:689–95.
  • ClinicalTrials.gov. A Phase 2 Exploratory Study of Erlotinib and SNDX-275 in Patients with Nonsmall Cell Lung Carcinoma who are Porgressing on Erlotinib. http://clinicaltrialsgov/ct2/show/NCT00750698?term=NCT00750698&rank=1 2011.
  • Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004;4:335–48.
  • Wang X, Hawk N, Yue P, Kauh J, Ramalingam SS, Fu H, Khuri FR, Sun SY. Overcoming mTOR inhibition-induced paradoxical activation of survival signaling pathways enhances mTOR inhibitors’ anticancer efficacy. Cancer Biol Ther 2008;7:1952–8.
  • Buck E, Eyzaguirre A, Brown E, Petti F, McCormack S, Haley JD, Iwata KK, Gibson NW, Griffin G. Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther 2006;5:2676–84.
  • Papadimitrakopoulou VA, William WN, Jr., Dannenberg AJ, Lippman SM, Lee JJ, Ondrey FG, Peterson DE, Feng L, Atwell A, El-Naggar AK, Nathan CO, Helman JI, Du B, Yueh B, Boyle JO. Pilot randomized phase II study of celecoxib in oral premalignant lesions. Clin Cancer Res 2008;14:2095–101.
  • ClinicalTrials.gov. A Combined Phase 1 and 2 Study Investigating the Combination of RAD001 and erlotinib in Patients with Advanced NSCLC previously treated only with Chemotherapy. http://clinicaltrialsgov/ct2/show/NCT00456833?term=NCT00456833&rank=1 2009.
  • Wissner A, Mansour TS. The development of HKI-272 and related compounds for the treatment of cancer. Arch Pharm (Weinheim) 2008;341:465–77.
  • Carter TA, Wodicka LM, Shah NP, Velasco AM, Fabian MA, Treiber DK, Milanov ZV, Atteridge CE, Biggs WH, 3rd, Edeen PT, Floyd M, Ford JM, Grotzfeld RM, Herrgard S, Insko DE, Mehta SA, Patel HK, Pao W, Sawyers CL, Varmus H, Zarrinkar PP, Lockhart DJ. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci USA 2005;102:11011–6.
  • Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, Padera RF, Shapiro GI, Baum A, Himmelsbach F, Rettig WJ, Meyerson M, Solca F, Greulich H, Wong KK. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008;27:4702–11.
  • Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, Zhao F, Vincent PW, Naumov GN, Bradner JE, Althaus IW, Gandhi L, Shapiro GI, Nelson JM, Heymach JV, Meyerson M, Wong KK, Janne PA. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007;67:11924–32.
  • Janne PA, von Pawel J, Cohen RB, Crino L, Butts CA, Olson SS, Eiseman IA, Chiappori AA, Yeap BY, Lenehan PF, Dasse K, Sheeran M, Bonomi PD. Multicenter, randomized, phase II trial of CI-1033, an irreversible pan-ERBB inhibitor, for previously treated advanced non small-cell lung cancer. J Clin Oncol 2007;25:3936–44.
  • Brabender J, Danenberg KD, Metzger R, Schneider PM, Park J, Salonga D, Holscher AH, Danenberg PV. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival. Clin Cancer Res 2001;7:1850–5.
  • Onn A, Correa AM, Gilcrease M, Isobe T, Massarelli E, Bucana CD, O'Reilly MS, Hong WK, Fidler IJ, Putnam JB, Herbst RS. Synchronous overexpression of epidermal growth factor receptor and HER2-neu protein is a predictor of poor outcome in patients with stage I non-small cell lung cancer. Clin Cancer Res 2004;10:136–43.
  • Tateishi M, Ishida T, Kohdono S, Hamatake M, Fukuyama Y, Sugimachi K. Prognostic influence of the co-expression of epidermal growth factor receptor and c-erbB-2 protein in human lung adenocarcinoma. Surg Oncol 1994;3:109–13.
  • Miller V, Hirsh V, Cadranel J, Chen Y, Park K, Kim S, Caicun Z, Oberdick M, Shahidi M, Yang C. Phase IIB/III double-blind randomized trial of afatinib (BIBW2992, an irreversible inhibitor of EGFR/HER1 and HER2) + best supportive care (BSC) versus placebo + BSC in patients with NSCLC failing 1–2 lines of chemotherapy and erlotinib or getitinib (LUX-LUNG 1). Ann Oncol 2010;21:viii1.
  • Yang C, Shih JY, Su WY, Hsia T, Tsai S, Ou I, Calvo R, Cong X, Shahidi M, Miller V. A phase II study of BIBW 2992 in patients with adenocarcinoma of the lung and activating EGFR mutations (LUX-Lung 2). J Clin Oncol 2010;28.
  • Yamamoto N, Katakami N, Atagi S, Hida T, Goto K, Horai T, Inoue A, Ichinose Y, Kobayashi K, Takeda K, Kiura K, Saka H, Tamura T, Okamoto I, Nogami N, Morinaga R, Nishio K, Seki Y, Lorence R, Shahidi M. A phase II trial of afatinib (BIBW 2992) in patients (pts) with advanced non-small cell lung cancer previously treated with erlotinib (E) or gefitinib (G). J Clin Oncol 2011;29.
  • De Greve DL, De Mey J. Clinical Activity of BIBW 2992, an Irreversible Inhibitor of EGFR/HER1 and HER2 in Adenocarcinoma of the Lung with Mutations in the Kinase Domain of Her2Neu. J Thorac Oncol 2010;5(5):s90.
  • ClinicalTrials.gov. Phase III Randomized Trial of BIBW 2992 plus Weekly Paclitaxel Versus Investigator's Choice of Chemotherapy following BIBW 2992 Monotherapy in Non-small cell lung cancer patients failing erlotinib or gefitinib. 2011.
  • ClinicalTrials.gov. LUX-Lung 6: A Randomized, Open-label, Phase III Study of BIBW 2992 Versus Chemotherapy as First-line Treatment for Patients with Stage IIIB or IV Adenocarcinoma of the Lung harbouring an EGFR Activating Mutation. http://clinicaltrials.gov/ct2/show/NCT01121393 2011.
  • Janjigian Y, Groen H, Horn L, Smit E, Fu Y, Wang F, Shahidi M, Denis L, Pao W, Miller V. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. J Clin Oncol 2011;29;15s (suppl abstr 7525).
  • Park K, Heo D, Cho B, Kim D, Ahn MJ, Lee S, Millham R, Campbell A, Zhang H, Kim J. PF-00299804 (PF299) in Asian atients (pts) with non-small cell lung cancer (NSCLC) refractory to chemotherapy (CT) and erlotinib (E) or gefitinib (G): A phase (P) I/II study. J Clin Oncol 2010;28.
  • Campbell A, Reckamp K, Camidge D, Giaccone G, Gadgeel S, Khuri F, Engelman J, Denis L, O'Connell J, Janne P. PF-00299804 (PF299) patient (pt) reported outcomes (PROs) and efficacy in adenocarcinoma (adeno) and nonadeno non-small cell lung cancer (NSCLC): a phase (P) II trial in advanced NSCLC after failure of chemotherapy (CT) and erlotinib (E). J Clin Oncol 2010;28:7596.
  • Janne P, Reckamp K, Koczywas M, Engelman J, Camidge D, Rajan A, Khuri FR, Liang J, O'Connell J, Giaccone G. Efficacy and safety of PF-00299804 (PF299) in patients (pt) with advanced NSCLC after failure of at least one prior chemotherapy regimen and prior treatment with erlotinib (E): A two-arm, phase II trial. J Clin Oncol 2009;27.
  • Boyer M, Blackhall F, Park K, Barrios C, Krzakowski M, Taylor I, Liang J, Denis L, O'Connell J, Ramalingam S. Efficacy and Safety of PF299804 versus Erlotinib: A global, randomized phase 2 trial in patients with advanced non-small cell lung cancer after failure of chemotherapy. J Clin Oncol 2010;28.
  • Mok T, Spigel DR, Park K, Efficacy and safety of PF-00299804 (PF299), an oral, irreversible, pan-human epidermal growth factor receptor (pan-HER) tyrosine kinase inhibitor (TKI), as first-line treatment (TX) of selected patients (pts) with advanced (adv) non-small cell lung cancer (NSCLC). J Clin Oncol 2010;28:7537.
  • ClinicalTrials.gov. A Double Blind Placebo Controlled Randomized Trial of PF-804 in Patients with Incurable Stage IIIB/IV Non-Small Cell Lung Cancer After Failure of Standard Therapy for Advanced or Metastatic Disease. http://clinicaltrials.gov/ct2/show/NCT01000025 2009.

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