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EGFR Mutant Lung Cancer

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Book cover Therapeutic Kinase Inhibitors

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 355))

Abstract

Thoracic oncologists traditionally have made treatment decisions based upon tumor histology, distinguishing non-small cell lung cancer (NSCLC) from small cell lung cancer (SCLC). However, recent data has revealed that at least one histological subtype of NSCLC, lung adenocarcinoma comprises multiple molecularly distinct diseases. Lung adenocarcinoma subsets now can be defined by specific ‘driver’ mutations in genes encoding components of the EGFR signaling pathway. Importantly, these mutations have implications regarding targeted therapy. Here, we focus on EGFR mutant NSCLC—a prime example of a clinically relevant molecular subset of lung cancer, with defined mechanisms of drug sensitivity, primary drug resistance, and acquired resistance to EGFR tyrosine kinase inhibitors. Efforts are now being made to overcome mechanisms of acquired resistance. These findings illustrate how knowledge about the genetic drivers of tumors can lead to rational targeted therapy for individual patients.

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References

  • Arcila ME, Oxnard GR, Nafa K, Riely GJ, Solomon SB, Zakowski MF, Kris MG, Pao W, Miller VA, Ladanyi M (2011) Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res 17:1169–1180. doi:10.1158/1078-0432.CCR-10-2277

    PubMed  CAS  Google Scholar 

  • Bahleda R, Felip E, Herbst RS, Hanna NH, Laurie SA, Shepherd FA, Armand JP, Sweeney CJ, Calvo-Aller E, Soria JC (2008) Phase I multicenter trial of BMS-690514: safety, pharmacokinetic profile, biological effects, and early clinical evaluation in patients with advanced solid tumors and non-small cell lung cancer. J Clin Oncol Meeting Abstracts

    Google Scholar 

  • Bahleda R, Soria J, Harbison C, Park J, Felip E, Hanna N, Laurie SA, Armand J, Shepherd FA, Herbst R (2009) Tumor regression and pharmacodynamic (PD) biomarker validation in non-small cell lung cancer (NSCLC) patients treated with the ErbB/VEGFR inhibitor BMS-690514. J Clin Oncol Meeting Abstracts

    Google Scholar 

  • 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 (2006) Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12:6494–6501

    PubMed  CAS  Google Scholar 

  • 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 (2007) 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 104:20932–20937. doi:10.1073/pnas.0710370104

    PubMed  CAS  Google Scholar 

  • Bean J, Riely GJ, Balak M, Marks JL, Ladanyi M, Miller VA, Pao W (2008) Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res 14:7519–7525. doi:10.1158/1078-0432.CCR-08-0151

    PubMed  CAS  Google Scholar 

  • Bell DW, Gore I, Okimoto RA, Godin-Heymann N, Sordella R, Mulloy R, Sharma SV, Brannigan BW, Mohapatra G, Settleman J, Haber DA (2005) Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet 37:1315–1316

    PubMed  CAS  Google Scholar 

  • Bivona TG, Hieronymus H, Parker J, Chang K, Taron M, Rosell R, Moonsamy P, Dahlman K, Miller VA, Costa C, Hannon G, Sawyers CL (2011) FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471:523–526. doi:10.1038/nature09870

    PubMed  CAS  Google Scholar 

  • Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y (2001) The new world health organization classification of lung tumours. Eur Respir J 18:1059–1068

    PubMed  CAS  Google Scholar 

  • Carey KD, Garton AJ, Romero MS, Kahler J, Thomson S, Ross S, Park F, Haley JD, Gibson N, Sliwkowski MX (2006) Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer Res 66:8163–8171. doi:10.1158/0008-5472.CAN-06-0453

    PubMed  CAS  Google Scholar 

  • Chmielecki J, Foo J, Oxnard GR, Hutchinson K, Ohashi K, Somwar R, Wang L, Amato KR, Arcila M, Sos ML, Socci ND, Viale A, de Stanchina E, Ginsberg MS, Thomas RK, Kris MG, Inoue A, Ladanyi M, Miller VA, Michor F, Pao W (2011) Optimization of dosing for EGFR mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med 3(90):90ra59

    PubMed  CAS  Google Scholar 

  • Chung JH, Rho JK, Xu X, Lee JS, Yoon HI, Lee CT, Choi YJ, Kim HR, Kim CH, Lee JC (2010) Clinical and molecular evidences of epithelial to mesenchymal transition in acquired resistance to EGFR-TKIs. Lung Cancer. doi:10.1016/j.lungcan.2010.11.011

  • Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R (2003) FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 8:303–306

    PubMed  CAS  Google Scholar 

  • Comoglio PM, Giordano S, Trusolino L (2008) Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 7:504–516. doi:10.1038/nrd2530

    PubMed  CAS  Google Scholar 

  • Cools J, Stover EH, Boulton CL, Gotlib J, Legare RD, Amaral SM, Curley DP, Duclos N, Rowan R, Kutok JL, Lee BH, Williams IR, Coutre SE, Stone RM, DeAngelo DJ, Marynen P, Manley PW, Meyer T, Fabbro D, Neuberg D, Weisberg E, Griffin JD, Gilliland DG (2003) PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRalpha-induced myeloproliferative disease. Cancer Cell 3:459–469

    PubMed  CAS  Google Scholar 

  • Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS, Boggon TJ, Tenen DG, Kobayashi S (2007) BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med 4:1669–1679. doi:10.1371/journal.pmed.0040315 discussion 1680

    PubMed  CAS  Google Scholar 

  • Costa DB, Schumer ST, Tenen DG, Kobayashi S (2008) Differential responses to erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancers with acquired resistance to gefitinib carrying the L747S or T790M secondary mutations. J Clin Oncol 26:1182–1184. doi:10.1200/JCO.2007.14.9039 author reply 1184-6

    PubMed  Google Scholar 

  • Cragg MS, Kuroda J, Puthalakath H, Huang DC, Strasser A (2007) Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med 4:1681–1689. doi:10.1371/journal.pmed.0040316 discussion 1690

    PubMed  CAS  Google Scholar 

  • de La Motte Rouge T, Galluzzi L, Olaussen KA, Zermati Y, Tasdemir E, Robert T, Ripoche H, Lazar V, Dessen P, Harper F, Pierron G, Pinna G, Araujo N, Harel-Belan A, Armand JP, Wong TW, Soria JC, Kroemer G (2007) A novel epidermal growth factor receptor inhibitor promotes apoptosis in non-small cell lung cancer cells resistant to erlotinib. Cancer Res 67:6253–6262. doi:10.1158/0008-5472.CAN-07-0538

    Google Scholar 

  • Dziadziuszko R, Camidge DR, Hirsch FR (2008) The insulin-like growth factor pathway in lung cancer. J Thorac Oncol 3:815–818. doi:10.1097/JTO.0b013e31818180f501243894-200808000-00003

    PubMed  Google Scholar 

  • Engelman JA, Janne PA, Mermel C, Pearlberg J, Mukohara T, Fleet C, Cichowski K, Johnson BE, Cantley LC (2005) ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA 102:3788–3793

    PubMed  CAS  Google Scholar 

  • 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 (2007a) PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 67:11924–11932. doi:10.1158/0008-5472.CAN-07-1885

    PubMed  CAS  Google Scholar 

  • 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 (2007b) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043. doi:10.1126/science.1141478

    PubMed  CAS  Google Scholar 

  • 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 (2003) 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 21:2237–2246

    PubMed  CAS  Google Scholar 

  • 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 (2007) 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 25:1545–1552. doi:10.1200/JCO.2005.05.1474

    PubMed  CAS  Google Scholar 

  • Gendreau SB, Ventura R, Keast P, Laird AD, Yakes FM, Zhang W, Bentzien F, Cancilla B, Lutman J, Chu F, Jackman L, Shi Y, Yu P, Wang J, Aftab DT, Jaeger CT, Meyer SM, De Costa A, Engell K, Chen J, Martini JF, Joly AH (2007) Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647. Clin Cancer Res 13:3713–3723. doi:10.1158/1078-0432.CCR-06-2590

    PubMed  CAS  Google Scholar 

  • 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 (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1. J Clin Oncol 22:777–784. doi:10.1200/JCO.2004.08.001JCO.2004.08.001

    PubMed  CAS  Google Scholar 

  • Godin-Heymann N, Ulkus L, Brannigan BW, McDermott U, Lamb J, Maheswaran S, Settleman J, Haber DA (2008) The T790M “gatekeeper” mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol Cancer Ther 7:874–879. doi:10.1158/1535-7163.MCT-07-2387

    PubMed  CAS  Google Scholar 

  • Gong Y, Somwar R, Politi K, Balak M, Chmielecki J, Jiang X, Pao W (2007) Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med 4:e294. doi:10.1371/journal.pmed.0040294

    PubMed  Google Scholar 

  • Gong Y, Yao E, Shen R, Goel A, Arcila M, Teruya-Feldstein J, Zakowski MF, Frankel S, Peifer M, Thomas RK, Ladanyi M, Pao W (2009) High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507). PLoS One 4:e7273. doi:10.1371/journal.pone.0007273

    PubMed  Google Scholar 

  • Gonzales AJ, Hook KE, Althaus IW, Ellis PA, Trachet E, Delaney AM, Harvey PJ, Ellis TA, Amato DM, Nelson JM, Fry DW, Zhu T, Loi CM, Fakhoury SA, Schlosser KM, Sexton KE, Winters RT, Reed JE, Bridges AJ, Lettiere DJ, Baker DA, Yang J, Lee HT, Tecle H, Vincent PW (2008) Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol Cancer Ther 7:1880–1889. doi:10.1158/1535-7163.MCT-07-2232

    PubMed  CAS  Google Scholar 

  • Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293(5531):876–880

    PubMed  CAS  Google Scholar 

  • Greulich H, Chen TH, Feng W, Janne PA, Alvarez JV, Zappaterra M, Bulmer SE, Frank DA, Hahn WC, Sellers WR, Meyerson M (2005) Oncogenic transformation by inhibitor-sensitive and resistant EGFR mutants. PLoS Med 2:e313

    PubMed  Google Scholar 

  • Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S, Rinehart C, Seidel B, Yee D, Arteaga CL, Engelman JA (2008) Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 118:2609–2619. doi:10.1172/JCI34588

    PubMed  CAS  Google Scholar 

  • Hartog H, Wesseling J, Boezen HM, van der Graaf WT (2007) The insulin-like growth factor 1 receptor in cancer: old focus, new future. Eur J Cancer 43:1895–1904. doi:10.1016/j.ejca.2007.05.021

    PubMed  CAS  Google Scholar 

  • 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 (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2. J Clin Oncol 22:785–794. doi:10.1200/JCO.2004.07.215

    PubMed  CAS  Google Scholar 

  • 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 (2005) 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 23:5892–5899. doi:10.1200/JCO.2005.02.840

    PubMed  CAS  Google Scholar 

  • Horn L, Pao W (2009) EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 27:4232–4235. doi:10.1200/JCO.2009.23.6661

    PubMed  CAS  Google Scholar 

  • Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354

    PubMed  CAS  Google Scholar 

  • Inoue A, Suzuki T, Fukuhara T, Maemondo M, Kimura Y, Morikawa N, Watanabe H, Saijo Y, Nukiwa T (2006) Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 24:3340–3346. doi:10.1200/JCO.2005.05.4692

    PubMed  CAS  Google Scholar 

  • Inukai M, Toyooka S, Ito S, Asano H, Ichihara S, Soh J, Suehisa H, Ouchida M, Aoe K, Aoe M, Kiura K, Shimizu N, Date H (2006) Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 66:7854–7858. doi:10.1158/0008-5472.CAN-06-1951

    PubMed  CAS  Google Scholar 

  • Jackman DM, Miller VA, Cioffredi LA, Yeap BY, Janne PA, Riely GJ, Ruiz MG, Giaccone G, Sequist LV, Johnson BE (2009) Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res 15:5267–5273. doi:10.1158/1078-0432.CCR-09-0888

    PubMed  CAS  Google Scholar 

  • Janjigian Y, Groen HJM, Horn L, Smit EF, Fu Y, Wang F, Shahidi M, Denis L, Pao W, Miller VA (2011) Activity and tolerability of afatinib (BIBW2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitnib. PASCO

    Google Scholar 

  • Janne P, Reckamp K, Koczywas M, Engelman JA, Camidge DR, Rajan A, Khuri F, Liang JQ, O’Connell J, Giaccone G (2009) 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 Meeting Abstracts

    Google Scholar 

  • Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249. doi:10.3322/caac.20006

    PubMed  Google Scholar 

  • Ji H, Zhao X, Yuza Y, Shimamura T, Li D, Protopopov A, Jung BL, McNamara K, Xia H, Glatt KA, Thomas RK, Sasaki H, Horner JW, Eck M, Mitchell A, Sun Y, Al-Hashem R, Bronson RT, Rabindran SK, Discafani CM, Maher E, Shapiro GI, Meyerson M, Wong KK (2006) Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors. Proc Natl Acad Sci USA 103:7817–7822

    PubMed  CAS  Google Scholar 

  • Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG (2009) Targeting MET as a strategy to overcome crosstalk-related resistance to EGFR inhibitors. Lancet Oncol 10:709–717. doi:10.1016/S1470-2045(09)70137-8

    PubMed  CAS  Google Scholar 

  • 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 (2008) Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372:1809–1818. doi:10.1016/S0140-6736(08)61758-4

    PubMed  CAS  Google Scholar 

  • Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792

    PubMed  CAS  Google Scholar 

  • 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 (2003) 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 290:2149–2158

    PubMed  CAS  Google Scholar 

  • 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 (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102:7665–7670

    PubMed  CAS  Google Scholar 

  • Li D, Shimamura T, Ji H, Chen L, Haringsma HJ, McNamara K, Liang MC, Perera SA, Zaghlul S, Borgman CL, Kubo S, Takahashi M, Sun Y, Chirieac LR, Padera RF, Lindeman NI, Janne PA, Thomas RK, Meyerson ML, Eck MJ, Engelman JA, Shapiro GI, Wong KK (2007) Bronchial and peripheral murine lung carcinomas induced by T790M–L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell 12:81–93. doi:10.1016/j.ccr.2007.06.005

    PubMed  CAS  Google Scholar 

  • 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 (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27:4702–4711. doi:10.1038/onc.2008.109

    PubMed  CAS  Google Scholar 

  • Linardou H, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D, Kosmidis P, Papadimitriou CA, Murray S (2008) 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 9:962–972. doi:10.1016/S1470-2045(08)70206-7

    PubMed  CAS  Google Scholar 

  • Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8:627–644. doi:10.1038/nrd2926

    PubMed  CAS  Google Scholar 

  • 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 (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139

    PubMed  CAS  Google Scholar 

  • 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 (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388. doi:10.1056/NEJMoa0909530

    PubMed  CAS  Google Scholar 

  • 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 (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359:366–377. doi:10.1056/NEJMoa0800668

    PubMed  CAS  Google Scholar 

  • Marks JL, Broderick S, Zhou Q, Chitale D, Li AR, Zakowski MF, Kris MG, Rusch VW, Azzoli CG, Seshan VE, Ladanyi M, Pao W (2008) Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol 3:111–116. doi:10.1097/JTO.0b013e318160c60701243894-200802000-00004

    PubMed  Google Scholar 

  • Mellinghoff I (2007) Why do cancer cells become “addicted” to oncogenic epidermal growth factor receptor? PLoS Med 4:1620–1622. doi:10.1371/journal.pmed.0040321

    PubMed  CAS  Google Scholar 

  • Miller V, Wakelee HA, Lara PN, Cho J, Chowhan NM, Costa D, Vrindavanam N, Yanagihara R, Pennell N, Lynch TJ (2008) Activity and tolerance of XL647 in NSCLC patients with acquired resistance to EGFR-TKIs: preliminary results of a phase II trial. J Clin Oncol Meeting Abstracts

    Google Scholar 

  • Miller VA, Hirsh V, Cadranel J, Chen Y-M, Park K, Kim S-W, Caicun Z, Oberdick M, Shahidi M, Yang C-H (2010) Phase IIB/III double-blind randomized trial of afatinib (BIBW 2992, 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 gefitinib (LUX-Lung 1). Annals of Oncol 21:LBA1

    Google Scholar 

  • 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 (2010) 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 11:121–128. doi:10.1016/S1470-2045(09)70364-X

    PubMed  CAS  Google Scholar 

  • 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 (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957. doi:10.1056/NEJMoa0810699

    PubMed  CAS  Google Scholar 

  • Moyer JD, Barbacci EG, Iwata KK, Arnold L, Boman B, Cunningham A, DiOrio C, Doty J, Morin MJ, Moyer MP, Neveu M, Pollack VA, Pustilnik LR, Reynolds MM, Sloan D, Theleman A, Miller P (1997) Induction of apoptosis and cell cycle arrest by CP-358, 774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57:4838–4848

    PubMed  CAS  Google Scholar 

  • Ogino A, Kitao H, Hirano S, Uchida A, Ishiai M, Kozuki T, Takigawa N, Takata M, Kiura K, Tanimoto M (2007) Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non small cell lung cancer cell line. Cancer Res 67:7807–7814. doi:10.1158/0008-5472.CAN-07-0681

    PubMed  CAS  Google Scholar 

  • O’Hare T, Walters DK, Stoffregen EP, Sherbenou DW, Heinrich MC, Deininger MW, Druker BJ (2005) Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib. Clin Cancer Res 11(19 Pt 1):6987–6993

    PubMed  Google Scholar 

  • Oxnard G, Arcila ME, Sima C, Riely GJ, Chmielecki J, Kris MG, Pao W, Ladanyi M, Miller VA (2011) 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 17(6):1616–1622. doi:10.1158/1078-0432.CCR-10-2692

    PubMed  CAS  Google Scholar 

  • 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 (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    PubMed  CAS  Google Scholar 

  • 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 (2004) 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 101:13306–13311

    PubMed  CAS  Google Scholar 

  • Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H (2005a) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73

    PubMed  Google Scholar 

  • Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, Zakowski MF, Heelan RT, Kris MG, Varmus HE (2005b) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17. doi:10.1371/journal.pmed.0020017

    PubMed  Google Scholar 

  • Politi K, Zakowski MF, Fan PD, Schonfeld EA, Pao W, Varmus HE (2006) Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev 20:1496–1510

    PubMed  CAS  Google Scholar 

  • Pratilas CA, Hanrahan AJ, Halilovic E, Persaud Y, Soh J, Chitale D, Shigematsu H, Yamamoto H, Sawai A, Janakiraman M, Taylor BS, Pao W, Toyooka S, Ladanyi M, Gazdar A, Rosen N, Solit DB (2008) Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 68:9375–9383. doi:10.1158/0008-5472.CAN-08-2223

    PubMed  CAS  Google Scholar 

  • Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A (2004) Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 64:3958–3965. doi:10.1158/0008-5472.CAN-03-2868

    PubMed  CAS  Google Scholar 

  • Regales L, Balak MN, Gong Y, Politi K, Sawai A, Le C, Koutcher JA, Solit DB, Rosen N, Zakowski MF, Pao W (2007) Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. PLoS One 2:e810. doi:10.1371/journal.pone.0000810

    PubMed  Google Scholar 

  • Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A, Koutcher JA, Spassova M, Ouerfelli O, Mellinghoff IK, Zakowski MF, Politi KA, Pao W (2009) Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest 119:3000–3010. doi:10.1172/JCI38746

    PubMed  CAS  Google Scholar 

  • Riely GJ, Pao W, Pham D, Li AR, Rizvi N, Venkatraman ES, Zakowski MF, Kris MG, Ladanyi M, Miller VA (2006) Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res 12:839–844. doi:10.1158/1078-0432.CCR-05-1846

    PubMed  CAS  Google Scholar 

  • Riely GJ, Kris MG, Zhao B, Akhurst T, Milton DT, Moore E, Tyson L, Pao W, Rizvi NA, Schwartz LH, Miller VA (2007) Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res 13:5150–5155. doi:10.1158/1078-0432.CCR-07-0560

    PubMed  CAS  Google Scholar 

  • Rizvi N, Kris MG, Miller VA, Krug LM, Bekele S, Dowlati A, Rowland KM, Salgia R, Aggarwal N, Gadgeel SM (2008) Activity of XL647 in clinically selected NSCLC patients (pts) enriched for the presence of EGFR mutations: results from phase 2. J Clin Oncol Meeting Abstracts

    Google Scholar 

  • 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 (2009a) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958–967. doi:10.1056/NEJMoa0904554

    PubMed  CAS  Google Scholar 

  • Rosell R, Perez-Roca L, Sanchez JJ, Cobo M, Moran T, Chaib I, Provencio M, Domine M, Sala MA, Jimenez U, Diz P, Barneto I, Macias JA, de Las Penas R, Catot S, Isla D, Sanchez JM, Ibeas R, Lopez-Vivanco G, Oramas J, Mendez P, Reguart N, Blanco R, Taron M (2009b) Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression. PLoS One 4:e5133. doi:10.1371/journal.pone.0005133

    PubMed  Google Scholar 

  • Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550. doi:10.1056/NEJMoa061884

    PubMed  CAS  Google Scholar 

  • Sawai A, Chandarlapaty S, Greulich H, Gonen M, Ye Q, Arteaga CL, Sellers W, Rosen N, Solit DB (2008) Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel. Cancer Res 68:589–596. doi:10.1158/0008-5472.CAN-07-1570

    PubMed  CAS  Google Scholar 

  • Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH TECOG (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98. doi:10.1056/NEJMoa011954346/2/92

    PubMed  CAS  Google Scholar 

  • Sequist L, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, Akhavanfard S, Heist RS, Temel J, Christensen J, Wain J, Lynch TJ, Vernovsky K, Mark EJ, Lanuti M, Iafrate AJ, Mino-Kenudson M, Engelman JA (2011) Genotypic and histological evolution of EGFR mutant NSCLCs upon development of resistance to EGFR kinase inhibitors. Science Transl Med

    Google Scholar 

  • Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Janne PA, Joshi VA, McCollum D, Evans TL, Muzikansky A, Kuhlmann GL, Han M, Goldberg JS, Settleman J, Iafrate AJ, Engelman JA, Haber DA, Johnson BE, Lynch TJ (2008) First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 26:2442–2449. doi:10.1200/JCO.2007.14.8494

    PubMed  CAS  Google Scholar 

  • Sequist LV, Besse B, Lynch TJ, Miller VA, Wong KK, Gitlitz B, Eaton K, Zacharchuk C, Freyman A, Powell C, Ananthakrishnan R, Quinn S, Soria JC (2010a) Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol 28:3076–3083. doi:10.1200/JCO.2009.27.9414

    PubMed  CAS  Google Scholar 

  • Sequist LV, Gettinger S, Senzer NN, Martins RG, Janne PA, Lilenbaum R, Gray JE, Iafrate AJ, Katayama R, Hafeez N, Sweeney J, Walker JR, Fritz C, Ross RW, Grayzel D, Engelman JA, Borger DR, Paez G, Natale R (2010b) Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol 28:4953–4960. doi:10.1200/JCO.2010.30.8338

    PubMed  CAS  Google Scholar 

  • Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, Sawyers CL (2002) Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2:117–125

    PubMed  CAS  Google Scholar 

  • Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181. doi:10.1038/nrc2088

    PubMed  CAS  Google Scholar 

  • Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U, Settleman J, Kobayashi S, Mark EJ, Rodig SJ, Chirieac LR, Kwak EL, Lynch TJ, Iafrate AJ (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247–4253. doi:10.1200/JCO.2009.22.6993

    PubMed  CAS  Google Scholar 

  • 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 (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132

    PubMed  CAS  Google Scholar 

  • Shih J, Yang C, Su W, Hsia T, Tsai C, Chen Y, Chang H, Terlizzi E, Shahidi M, Miller VA (2009) A phase II study of BIBW 2992, a novel irreversible dual EGFR and HER2 tyrosine kinase inhibitor (TKI), in patients with adenocarcinoma of the lung and activating EGFR mutations after failure of one line of chemotherapy (LUX-Lung 2). J Clin Oncol Meeting Abstracts

    Google Scholar 

  • Shimamura T, Lowell AM, Engelman JA, Shapiro GI (2005) Epidermal growth factor receptors harboring kinase domain mutations associate with the heat shock protein 90 chaperone and are destabilized following exposure to geldanamycins. Cancer Res 65:6401–6408. doi:10.1158/0008-5472.CAN-05-0933

    PubMed  CAS  Google Scholar 

  • Shimamura T, Li D, Ji H, Haringsma HJ, Liniker E, Borgman CL, Lowell AM, Minami Y, McNamara K, Perera SA, Zaghlul S, Thomas RK, Greulich H, Kobayashi S, Chirieac LR, Padera RF, Kubo S, Takahashi M, Tenen DG, Meyerson M, Wong KK, Shapiro GI (2008) Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance. Cancer Res 68:5827–5838. doi:10.1158/0008-5472.CAN-07-5428

    PubMed  CAS  Google Scholar 

  • 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 (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566. doi:10.1038/nature05945

    PubMed  CAS  Google Scholar 

  • Soria JC, Lee HY, Lee JI, Wang L, Issa JP, Kemp BL, Liu DD, Kurie JM, Mao L, Khuri FR (2002) Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res 8:1178–1184

    PubMed  CAS  Google Scholar 

  • Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, Zander T, Seeger JM, Weiss J, Fischer F, Frommolt P, Michel K, Peifer M, Mermel C, Girard L, Peyton M, Gazdar AF, Minna JD, Garraway LA, Kashkar H, Pao W, Meyerson M, Thomas RK (2009) PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69:3256–3261. doi:10.1158/0008-5472.CAN-08-4055

    PubMed  CAS  Google Scholar 

  • Stamos J, Sliwkowski MX, Eigenbrot C (2002) Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 277:46265–46272

    PubMed  CAS  Google Scholar 

  • Sunaga N, Tomizawa Y, Yanagitani N, Iijima H, Kaira K, Shimizu K, Tanaka S, Suga T, Hisada T, Ishizuka T, Saito R, Dobashi K, Mori M (2007) Phase II prospective study of the efficacy of gefitinib for the treatment of stage III/IV non-small cell lung cancer with EGFR mutations, irrespective of previous chemotherapy. Lung Cancer 56:383–389. doi:10.1016/j.lungcan.2007.01.025

    PubMed  Google Scholar 

  • Tamborini E, Bonadiman L, Greco A, Albertini V, Negri T, Gronchi A, Bertulli R, Colecchia M, Casali PG, Pierotti MA, Pilotti S (2004) A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 127:294–299. doi:S0016508504002203

    PubMed  CAS  Google Scholar 

  • Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, Iwata KK, Gibson N, Haley JD (2005) 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 65:9455–9462. doi:10.1158/0008-5472.CAN-05-1058

    PubMed  CAS  Google Scholar 

  • Toyooka S, Kiura K, Mitsudomi T (2005) EGFR mutation and response of lung cancer to gefitinib. N Engl J Med 352:2136. doi:10.1056/NEJM200505193522019 author reply 2136

    PubMed  CAS  Google Scholar 

  • Uramoto H, Iwata T, Onitsuka T, Shimokawa H, Hanagiri T, Oyama T (2010) Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma. Anticancer Res 30:2513–2517

    PubMed  CAS  Google Scholar 

  • Wakeling AE, Guy SP, Woodburn JR, Ashton SE, Curry BJ, Barker AJ, Gibson KH (2002) ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 62:5749–5754

    PubMed  CAS  Google Scholar 

  • Wong KK (2007) HKI-272 in non small cell lung cancer. Clin Cancer Res 13:s4593–s4596. doi:10.1158/1078-0432.CCR-07-0369

    PubMed  Google Scholar 

  • Wong T, Ayers M, Emanuel S, Fargnoli J, Harbison C, Lee F, Oppenheimer S, Yu C, Krishnan B, Zhang H, Chen P, Fink B, Norris D, Vite G, Gavai A (2007) Inhibition of EGFR/HER2 signaling in tumor cells and VEGFR2 activity in tumor endothelium contribute to the preclinical anti-tumor activity of BMS-690514. AACR Meeting Abstracts

    Google Scholar 

  • Wu JY, Wu SG, Yang CH, Gow CH, Chang YL, Yu CJ, Shih JY, Yang PC (2008) Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res 14:4877–4882. doi:10.1158/1078-0432.CCR-07-5123

    PubMed  CAS  Google Scholar 

  • Yang C, Shih J, Chao T, Tsai C, Yu C, Yang P, Streit M, Shahidi M, Miller VA (2008) Use of BIBW 2992, a novel irreversible EGFR/HER2 TKI, to induce regression in patients with adenocarcinoma of the lung and activating EGFR mutations: preliminary results of a single-arm phase II clinical trial. J Clin Oncol Meeting Abstracts

    Google Scholar 

  • 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 (2008) Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res 68:9479–9487. doi:10.1158/0008-5472.CAN-08-1643

    PubMed  CAS  Google Scholar 

  • Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ (2008) The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 105:2070–2075. doi:10.1073/pnas.0709662105

    PubMed  CAS  Google Scholar 

  • Zakowski MF, Ladanyi M, Kris MG (2006) EGFR mutations in small-cell lung cancers in patients who have never smoked. N Engl J Med 355:213–215. doi:10.1056/NEJMc053610

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the NIH National Cancer Institute (NCI) grants R01-CA121210, P01CA129243, P50-CA90949, and P30-CA68485, and Joan’s legacy: the Joan Scarangello Foundation to conquer lung cancer.

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  1. Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

    Yixuan Gong

  2. Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    William Pao

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  1. Yixuan Gong
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Correspondence to William Pao .

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  1. , Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, York Avenue 1275, New York, 10065, New York, USA

    Ingo K. Mellinghoff

  2. , Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, York Avenue 1275, New York, 10065, New York, USA

    Charles L. Sawyers

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Gong, Y., Pao, W. (2011). EGFR Mutant Lung Cancer. In: Mellinghoff, I., Sawyers, C. (eds) Therapeutic Kinase Inhibitors. Current Topics in Microbiology and Immunology, vol 355. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2011_171

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