Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma
Keywords:Non-small cell lung cancer, EGFR, EML4-ALK, tyrosine kinase inhibitors, drug resistance, ABC transporters, ABCB1, ABCC1, ABCC10, ABCG2.
Lung cancer is the most commonly diagnosed cancer in the world. “Driver” and “passenger” mutations identified in lung cancer indicate that genetics play a major role in the development of the disease, progression, metastasis and response to therapy. Survival rates for lung cancer treatment have remained stagnant at ~15% over the past 40 years in patients with disseminated disease despite advances in surgical techniques, radiotherapy and chemotherapy. Resistance to therapy; either intrinsic or acquired has been a major hindrance to treatment leading to great interest in studies seeking to understand and overcome resistance. Genetic information gained from molecular analyses has been critical in identifying druggable targets and tumor profiles that may be predictors of therapeutic response and mediators of resistance. Mutated or overexpressed epidermal growth factor receptor (EGFR) and translocations in the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) genes (EML4-ALK) are examples of genetic aberrations resulting in targeted therapies for both localized and metastatic disease. Positive clinical responses have been noted in patients harboring these genetic mutations when treated with targeted therapies compared to patients lacking these mutations. Resistance is nonetheless a major factor contributing to the failure of targeted agents and standard cytotoxic agents. In this review, we examine molecular mechanisms that are potential drivers of resistance in non-small cell lung carcinoma, the most frequently diagnosed form of lung cancer. The mechanisms addressed include resistance to molecular targeted therapies as well as conventional chemotherapeutics through the activity of multidrug resistance proteins.
Jemal A, et al. Global cancer statistics. CA Cancer J Clin 2011; 61(2): 69-90. http://dx.doi.org/10.3322/caac.20107
Siegel RD. Naishadham, Jemal A. Cancer statistics 2012. CA Cancer J Clin 2012; 62(1): 10-29. http://dx.doi.org/10.3322/caac.20138
Vineis P, et al. Tobacco and cancer: recent epidemiological evidence. J Natl Cancer Inst 2004; 96(2): 99-106. http://dx.doi.org/10.1093/jnci/djh014
Hang B. Formation and repair of tobacco carcinogen-derived bulky DNA adducts. J Nucleic Acids 2010; 2010: 709521.
Parkin DM. Tobacco-attributable cancer burden in the UK in 2010. Br J Cancer 2011; 105(Suppl 2): S6-S13. http://dx.doi.org/10.1038/bjc.2011.475
Takahashi H, et al. Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell 2010; 17(1): 89-97. http://dx.doi.org/10.1016/j.ccr.2009.12.008
Burlakova EB, et al. Biomarkers of oxidative stress and smoking in cancer patients. J Cancer Res Ther 2010; 6(1): 47-53. http://dx.doi.org/10.4103/0973-1482.63569
Hecht SS. Lung carcinogenesis by tobacco smoke. Int J Cancer 2012; 131(12): 2724-32. http://dx.doi.org/10.1002/ijc.27816
Rosenberger A, et al. Do genetic factors protect for early onset lung cancer? A case control study before the age of 50 years. BMC Cancer 2008; 8: 60. http://dx.doi.org/10.1186/1471-2407-8-60
Bromen K, et al. Aggregation of lung cancer in families: results from a population-based case-control study in Germany. Am J Epidemiol 2000; 152(6): 497-505. http://dx.doi.org/10.1093/aje/152.6.497
Etzel CJ, Amos CI, Spitz MR. Risk for smoking-related cancer among relatives of lung cancer patients. Cancer Res 2003; 63(23): 8531-5.
Amos CI, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 2008; 40(5): 616-22. http://dx.doi.org/10.1038/ng.109
Brennan P, Hainaut P, Boffetta P. Genetics of lung-cancer susceptibility. Lancet Oncol 2011; 12(4): 399-408. http://dx.doi.org/10.1016/S1470-2045(10)70126-1
American Cancer Society, Cancer facts & figures 2013: Atlanta.
Ettinger DS, et al. Non-small cell lung cancer. J Natl Compr Canc Netw 2010; 8(7): 740-801.
Cetin K, et al. Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the Surveillance, Epidemiology and End Results Program. Clin Epidemiol 2011; 3: 139-48.
D’Arcangelo M; Cappuzzo F. K-Ras Mutations in Non-Small-Cell Lung Cancer: Prognostic and Predictive Value. ISRN Mol Biol 2012; 2012: 8.
Howlader N, et al. SEER Cancer Statistics Review 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_ pops09/, based on November 2011 SEER data submission, posted to the SEER web site, April 2012; 2012.
Aisner DL, Marshall CB. Molecular pathology of non-small cell lung cancer: a practical guide. Am J Clin Pathol 2012; 138(3): 332-46. http://dx.doi.org/10.1309/AJCPFR12WJKCEEZZ
Travis WD, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6(2): 244-85. http://dx.doi.org/10.1097/JTO.0b013e318206a221
Crino L, et al. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21(Suppl 5): v103-15. http://dx.doi.org/10.1093/annonc/mdq207
Goldstraw P, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007; 2(8): 706-14. http://dx.doi.org/10.1097/JTO.0b013e31812f3c1a
Chansky K, et al. The International Association for the Study of Lung Cancer Staging Project: prognostic factors and pathologic TNM stage in surgically managed non-small cell lung cancer. J Thorac Oncol 2009; 4(7): 792-801. http://dx.doi.org/10.1097/JTO.0b013e3181a7716e
Winton T, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352(25): 2589-97. http://dx.doi.org/10.1056/NEJMoa043623
Kelsey CR, Clough RW, Marks LB. Local recurrence following initial resection of NSCLC: salvage is possible with radiation therapy. Cancer J 2006; 12(4): 283-8. http://dx.doi.org/10.1097/00130404-200607000-00006
Pfister DG, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004; 22(2): 330-53. http://dx.doi.org/10.1200/JCO.2004.09.053
Xu Y, et al. Concomitant chemoradiotherapy using pemetrexed and carboplatin for unresectable stage III non-small cell lung cancer (NSCLC): preliminary results of a phase II study. Lung Cancer 2011; 72(3): 327-32. http://dx.doi.org/10.1016/j.lungcan.2010.09.012
Azzoli CG, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009; 27(36): 6251-66. http://dx.doi.org/10.1200/JCO.2009.23.5622
Goffin J, et al. First-line systemic chemotherapy in the treatment of advanced non-small cell lung cancer: a systematic review. J Thorac Oncol 2010; 5(2): 260-74. http://dx.doi.org/10.1097/JTO.0b013e3181c6f035
Schnabel PA, et al. Influence of histology and biomarkers on first-line treatment of advanced non-small cell lung cancer in routine care setting: baseline results of an observational study (FRAME). Lung Cancer 2012; 78(3): 263-9. http://dx.doi.org/10.1016/j.lungcan.2012.09.001
Ohe Y, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007; 18(2): 317-23. http://dx.doi.org/10.1093/annonc/mdl377
Ma PC. Personalized targeted therapy in advanced non-small cell lung cancer. Cleve Clin J Med 2012; 79 Electronic Suppl 1: eS56-60.
Mitsudomi T, et al. 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(2): 121-8. http://dx.doi.org/10.1016/S1470-2045(09)70364-X
Fukuoka M, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011; 29(21): 2866-74. http://dx.doi.org/10.1200/JCO.2010.33.4235
Lynch TJ, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350(21): 2129-39. http://dx.doi.org/10.1056/NEJMoa040938
Soda M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448(7153): 561-6. http://dx.doi.org/10.1038/nature05945
Riely GJ, Ladanyi M. KRAS mutations: an old oncogene becomes a new predictive biomarker. J Mol Diagn 2008; 10(6): 493-5. http://dx.doi.org/10.2353/jmoldx.2008.080105
Rekhtman N, et al. Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res 2012; 18(4): 1167-76. http://dx.doi.org/10.1158/1078-0432.CCR-11-2109
Lippert TH, Ruoff HJ, Volm M. Current status of methods to assess cancer drug resistance. Int J Med Sci 2011; 8(3): 245-53. http://dx.doi.org/10.7150/ijms.8.245
Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med 2002; 53: 615-27. http://dx.doi.org/10.1146/annurev.med.53.082901.103929
Mellor HR, Callaghan R. Resistance to chemotherapy in cancer: a complex and integrated cellular response. Pharmacology 2008; 81(4): 275-300. http://dx.doi.org/10.1159/000115967
Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005; 5(5): 341-54. http://dx.doi.org/10.1038/nrc1609
Baselga J, Albanell J. Targeting epidermal growth factor receptor in lung cancer. Curr Oncol Rep 2002; 4(4): 317-24. http://dx.doi.org/10.1007/s11912-002-0007-1
Chen G, et al. Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab. BMC Med 2012; 10: 28. http://dx.doi.org/10.1186/1741-7015-10-28
Sridhar SS, Seymour L, Shepherd FA. Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer. Lancet Oncol 2003; 4(7): 397-406. http://dx.doi.org/10.1016/S1470-2045(03)01137-9
Jorissen RN, et al. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 2003; 284(1): 31-53. http://dx.doi.org/10.1016/S0014-4827(02)00098-8
Sibilia M, et al. The epidermal growth factor receptor: from development to tumorigenesis. Differentiation 2007; 75(9): 770-87. http://dx.doi.org/10.1111/j.1432-0436.2007.00238.x
Uberall I, et al. The status and role of ErbB receptors in human cancer. Exp Mol Pathol 2008; 84(2): 79-89. http://dx.doi.org/10.1016/j.yexmp.2007.12.002
Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 2012; 12(8): 553-63. http://dx.doi.org/10.1038/nrc3309
Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer 2002; 94(5): 1593-11. http://dx.doi.org/10.1002/cncr.10372
Grandis JR, Sok JC. Signaling through the epidermal growth factor receptor during the development of malignancy. Pharmacol Ther 2004; 102(1): 37-46. http://dx.doi.org/10.1016/j.pharmthera.2004.01.002
Hirsch FR, Varella-Garcia M, Cappuzzo F. Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. Oncogene 2009; 28(Suppl 1): S32-7. http://dx.doi.org/10.1038/onc.2009.199
Sequist LV, et al. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 2007; 25(5): 587-95. http://dx.doi.org/10.1200/JCO.2006.07.3585
Sharma SV, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007; 7(3): 169-81. http://dx.doi.org/10.1038/nrc2088
Ono M, Kuwano M. Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res 2006; 12(24): 7242-51. http://dx.doi.org/10.1158/1078-0432.CCR-06-0646
Pirker R, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012; 13(1): 33-42. http://dx.doi.org/10.1016/S1470-2045(11)70318-7
Milas I, et al. Epidermal growth factor receptor, cyclooxygenase-2, and BAX expression in the primary non-small cell lung cancer and brain metastases. Clin Cancer Res 2003; 9(3): 1070-6.
Perez-Soler R. Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) in non-small-cell lung cancer. Clin Lung Cancer 2004; 6(Suppl 1): S20-3. http://dx.doi.org/10.3816/CLC.2004.s.010
Shepherd FA, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353(2): 123-32. http://dx.doi.org/10.1056/NEJMoa050753
Chang A, et al. Gefitinib (IRESSA) in patients of Asian origin with refractory advanced non-small cell lung cancer: subset analysis from the ISEL study. J Thorac Oncol 2006; 1(8): 847-55. http://dx.doi.org/10.1097/01243894-200610000-00014
Rosell R, et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann Oncol 2008; 19(2): 362-9. http://dx.doi.org/10.1093/annonc/mdm474
Jackman DM, et al. 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 2009; 15(16): 5267-73. http://dx.doi.org/10.1158/1078-0432.CCR-09-0888
Lin L, Bivona T. Mechanisms of Resistance to Epidermal Growth Factor Receptor Inhibitors and Novel Therapeutic Strategies to Overcome Resistance in NSCLC Patients. Chemother Res Pract 2012; 2012: 817297.
Bell DW, et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet 2005; 37(12): 1315-6. http://dx.doi.org/10.1038/ng1671
Pao W, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005; 2(3): e73. http://dx.doi.org/10.1371/journal.pmed.0020073
Kobayashi S, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005; 352(8): 786-92. http://dx.doi.org/10.1056/NEJMoa044238
Sos ML, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 2009; 69(8): 3256-61. http://dx.doi.org/10.1158/0008-5472.CAN-08-4055
She QB, et al. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 2005; 8(4): 287-97. http://dx.doi.org/10.1016/j.ccr.2005.09.006
Vivanco I, et al. The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation. Proc Natl Acad Sci USA 2010; 107(14): 6459-64. http://dx.doi.org/10.1073/pnas.0911188107
Yamamoto H, et al. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 2008; 68(17): 6913-21. http://dx.doi.org/10.1158/0008-5472.CAN-07-5084
Ludovini V, et al. High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients. Ann Oncol 2009; 20(5): 842-9. http://dx.doi.org/10.1093/annonc/mdn727
Cortot AB, et al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res 2013; 73(2): 834-43. http://dx.doi.org/10.1158/0008-5472.CAN-12-2066
Sharma SV, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010; 141(1): 69-80. http://dx.doi.org/10.1016/j.cell.2010.02.027
Boch C, et al. The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study. BMJ Open 2013; 3(4).
Brugger W, et al. Prospective Molecular Marker Analyses of EGFR and KRAS From a Randomized, Placebo-Controlled Study of Erlotinib Maintenance Therapy in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2011. http://dx.doi.org/10.1200/JCO.2010.31.8162
Eberhard DA, et al. 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(25): 5900-9. http://dx.doi.org/10.1200/JCO.2005.02.857
Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc 2009; 6(2): 201-5. http://dx.doi.org/10.1513/pats.200809-107LC
Heinemann V, et al. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev 2009; 35(3): 262-71. http://dx.doi.org/10.1016/j.ctrv.2008.11.005
Rodenhuis S, et al. Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med 1987; 317(15): 929-35. http://dx.doi.org/10.1056/NEJM198710083171504
Westra WH, et al. K-ras oncogene activation in lung adenocarcinomas from former smokers. Evidence that K-ras mutations are an early and irreversible event in the development of adenocarcinoma of the lung. Cancer 1993; 72(2): 432-8. http://dx.doi.org/10.1002/1097-0142(19930715)72:2<432::AID-CNCR2820720219>3.0.CO;2-
Bos JL, RAS oncogenes in human cancer: a review. Cancer Res 1989; 49(17): 4682-9.
Riely GJ, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 2008; 14(18): 5731-4. http://dx.doi.org/10.1158/1078-0432.CCR-08-0646
Ahrendt SA, et al. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer 2001; 92(6): 1525-30. http://dx.doi.org/10.1002/1097-0142(20010915)92:6<1525::AID-CNCR1478>3.0.CO;2-H
Pao W, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005; 2(1): e17. http://dx.doi.org/10.1371/journal.pmed.0020017
Garcia J, et al. KRAS mutational testing in the selection of patients for EGFR-targeted therapies. Semin Diagn Pathol 2008; 25(4): 288-94. http://dx.doi.org/10.1053/j.semdp.2008.08.003
Mascaux C, et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 2005; 92(1): 131-9. http://dx.doi.org/10.1038/sj.bjc.6602258
Zhu CQ, et al. 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(26): 4268-75. http://dx.doi.org/10.1200/JCO.2007.14.8924
van Zandwijk N, et al. EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Ann Oncol 2007; 18(1): 99-103. http://dx.doi.org/10.1093/annonc/mdl323
Douillard JY, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 2010; 28(5): 744-52. http://dx.doi.org/10.1200/JCO.2009.24.3030
Janne PA, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013; 14(1): 38-47. http://dx.doi.org/10.1016/S1470-2045(12)70489-8
Heuckmann JM, Rauh D, Thomas RK, Epidermal growth factor receptor (EGFR) signaling and covalent EGFR inhibition in lung cancer. J Clin Oncol 2012; 30(27): 3417-20. http://dx.doi.org/10.1200/JCO.2012.43.1825
Riely GJ, et al. 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 2007; 13(17): 5150-5. http://dx.doi.org/10.1158/1078-0432.CCR-07-0560
Yun CH, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 2008; 105(6): 2070-5. http://dx.doi.org/10.1073/pnas.0709662105
Yun CH, et al. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 2007; 11(3): 217-27. http://dx.doi.org/10.1016/j.ccr.2006.12.017
Azam M, et al. Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat Struct Mol Biol 2008; 15(10): 1109-18. http://dx.doi.org/10.1038/nsmb.1486
Carter TA, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci USA 2005; 102(31): 11011-6. http://dx.doi.org/10.1073/pnas.0504952102
Balak MN, et al. 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(21): 6494-501. http://dx.doi.org/10.1158/1078-0432.CCR-06-1570
Costa DB, et al. 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 2008; 26(7): 1182-4; author reply 1184-6. http://dx.doi.org/10.1200/JCO.2007.14.9039
Bean J, et al. 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 2008; 14(22): 7519-25. http://dx.doi.org/10.1158/1078-0432.CCR-08-0151
Leguay T, et al. D276G mutation is associated with a poor prognosis in imatinib mesylate-resistant chronic myeloid leukemia patients. Leukemia 2005; 19(12): 2332-3; author reply 2333-4. http://dx.doi.org/10.1038/sj.leu.2403993
Kwak EL, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 2005; 102(21): 7665-70. http://dx.doi.org/10.1073/pnas.0502860102
Ramalingam S.S, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2012; 30(27): 3337-44. http://dx.doi.org/10.1200/JCO.2011.40.9433
Janne PA, et al. Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res 2011; 17(5): 1131-9. http://dx.doi.org/10.1158/1078-0432.CCR-10-1220
Li D, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27(34): 4702-11. http://dx.doi.org/10.1038/onc.2008.109
Miller VA, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012; 13(5): 528-38. http://dx.doi.org/10.1016/S1470-2045(12)70087-6
Yang JC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol 2012; 13(5): 539-48. http://dx.doi.org/10.1016/S1470-2045(12)70086-4
Yeh HH, et al. Molecular imaging of active mutant L858R EGF receptor (EGFR) kinase-expressing nonsmall cell lung carcinomas using PET/CT. Proc Natl Acad Sci USA 2011; 108(4): 1603-8. http://dx.doi.org/10.1073/pnas.1010744108
Sequist LV, et al. 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 2010; 28(18): 3076-83. http://dx.doi.org/10.1200/JCO.2009.27.9414
Thiery JP, Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003; 15(6): 740-6. http://dx.doi.org/10.1016/j.ceb.2003.10.006
Xiao D, He J. Epithelial mesenchymal transition and lung cancer. J Thorac Dis 2010; 2(3): 154-9.