medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.medsovet-2164Research ArticleТАРГЕТНАЯ ТЕРАПИЯ ОПУХОЛЕЙTarget therapy of tumorsПРИОБРЕТЕННАЯ РЕЗИСТЕНТНОСТЬ К ИНГИБИТОРАМ ТИРОЗИНКИНАЗЫ EGFR: ПУТИ ПРЕОДОЛЕНИЯРеутоваЕ. В.

Кандидат медицинских наук.

Москва

ЛактионовК. К.

Доктор медицинских наук,  профессор.

Москва

АрдзинбаМ. С.

Кандидат медицинских наук.

Москва

НелюбинаЛ. А.

Кандидат медицинских наук.

Москва

АрзуманянА. Л.

Кандидат медицинских наук.

Москва

Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина Минздрава РоссииRussian Federation2017141120170142428Copyright © Реутова Е.В., Лактионов К.К., Ардзинба М.С., Нелюбина Л.А., Арзуманян А.Л., 20172017Реутова Е.В., Лактионов К.К., Ардзинба М.С., Нелюбина Л.А., Арзуманян А.Л.Реутова Е.В., Лактионов К.К., Ардзинба М.С., Нелюбина Л.А., Арзуманян А.Л.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/2164

Успехи в лечении диссеминированных больных с немелкоклеточным раком легкого напрямую связаны с таргетной терапией. Пациенты с активирующими мутациями в гене рецептора эпидермального фактора роста (EGFR) при назначении им в первую линию ингибиторов тирозинкиназы EGFR (ТКИ  EGFR) первого и второго поколений имеют достоверное преимущество по непосредственной эффективности и времени до прогрессирования. Кроме того, у больных с делецией в 19 экзоне EGFR, получающих афатиниб, общая выживаемость достигает 30  мес., что статистически  выше по сравнению со стандартной химиотерапией. Однако в течение 10–12 мес. развивается приобретенная резистентность к таргетным препаратам, основной причиной которой в 60% случаев является мутация Т790М. Осимертиниб – ТКИ третьего поколения, оказался высокоэффективен именно у этих больных. Для уточнения механизма резистентности требуется повторное молекулярно-генетическое тестирование. Таким образом, необходима повторная биопсия опухоли, оптимально из очага прогрессирования. К сожалению, это не всегда выполнимо, и альтернативой может быть жидкостная биопсия. Только такой индивидуальный подход может обеспечить выбор оптимальной лечебной тактики и добиться улучшения выживаемости пациентов.

Advances in the treatment of disseminated patients with non-small cell lung cancer are directly linked to targeted therapy. Patients with activating mutations in the gene for the receptor of epidermal growth factor  (EGFR) in appointing them in the first line EGFR tyrosine kinase inhibitors (EGFR TKI) of the first and second generations have a significant preference for immediate efficacy and time to progression. In addition, patients with a deletion in exon 19 of EGFR receiving afatinib, overall survival reached 30 months, which is statistically higher compared to standard chemotherapy. However, during the 10–12 months developing acquired resistance to targeted drugs. The main reason which in 60% of cases is a mutation Т790М. Osimertinib – TKI third-generation proved to be highly effective  in these  patients. To clarify the mechanism of resistance requires repeated molecular genetic testing. Thus, you need to re-biopsy the tumor, optimally from the source of progression. Unfortunately, it is not always possible and an alternative may be a liquid biopsy. Only such an individual approach can provide a choice of optimum treatment tactics and improve patient survival.

немелкоклеточный рак легкогоEGFRингибиторы тирозинкиназы EGFRрезистентностьосимертинибnon-small cell lung cancerEGFRtyrosine kinase inhibitors of EGFRresistanceosimertinibReferencesТюляндин С.А., Имянитов Е.Н., Моисеенко В.М., Пономаренко Д.М., Гурина Л.И., Королева И.А., Карасева В.В. Терапия больных немелкоклеточным раком легкого в Российской Федерации: исследование EPICLIN-Lung. Современная онкология, 2016, 04: 27-33.Тюляндин С.А., Имянитов Е.Н., Моисеенко В.М., Пономаренко Д.М., Гурина Л.И., Королева И.А., Карасева В.В. Терапия больных немелкоклеточным раком легкого в Российской Федерации: исследование EPICLIN-Lung. Современная онкология, 2016, 04: 27-33.Antonicelli A, Cafarotti S, Indini A et al. EGFRtargeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci, 2013, 10: 320-330.Antonicelli A, Cafarotti S, Indini A et al. EGFRtargeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci, 2013, 10: 320-330.Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 2009, 361(10): 947-957.Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 2009, 361(10): 947-957.Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT et al. First-SIGNAL: first-line single-agent iressa versus gemcitabineand cisplatin trial in neversmokers with adenocarcinoma of the lung. J Clin Oncol, 2012, 30(10): 1122-1128.Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT et al. First-SIGNAL: first-line single-agent iressa versus gemcitabineand cisplatin trial in neversmokers with adenocarcinoma of the lung. J Clin Oncol, 2012, 30(10): 1122-1128.Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S,Isobe H et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol, 2013, 24(1): 54-59.Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S,Isobe H et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol, 2013, 24(1): 54-59.Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med, 2010, 362(25): 2380-2388.Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med, 2010, 362(25): 2380-2388.Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J et al. Gefitinib versus cisplatin plus docetaxel in patients ManagementMitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J et al. Gefitinib versus cisplatin plus docetaxel in patients Managementof Adverse Events from EGFR Tyrosine Kinase Inhibitors 1347 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): 121-128.of Adverse Events from EGFR Tyrosine Kinase Inhibitors 1347 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): 121-128.Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, openlabel, randomised, phase 3 study. Lancet Oncol, 2011, 12(8): 735-742.Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, openlabel, randomised, phase 3 study. Lancet Oncol, 2011, 12(8): 735-742.Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-posi-tive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol, 2012, 13(3): 239-246.Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-posi-tive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol, 2012, 13(3): 239-246.Majem M, Remon J. Tumor heterogeneity: evolution through space and time in EGFR mutant non small cell lung cancer patients. Lung Cancer Res, 2013, 226-237.Majem M, Remon J. Tumor heterogeneity: evolution through space and time in EGFR mutant non small cell lung cancer patients. Lung Cancer Res, 2013, 226-237.Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol, 2012, 13: e23-31.Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol, 2012, 13: e23-31.Rosell R, Molina MA, Costa C et al. Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced nonsmall-cell lung cancer patients with EGFR mutations. Clin Cancer Res, 2011, 17: 1160-1168.Rosell R, Molina MA, Costa C et al. Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced nonsmall-cell lung cancer patients with EGFR mutations. Clin Cancer Res, 2011, 17: 1160-1168.Rosell R, Molina-Vila MA, Taron M et al. EGFR compound mutants and survival on erlotinib in non-small cell lung cancer (NSCLC) patients (p) in the EURTAC study. J Clin Oncol, 2012, 30: abstr 7522.Rosell R, Molina-Vila MA, Taron M et al. EGFR compound mutants and survival on erlotinib in non-small cell lung cancer (NSCLC) patients (p) in the EURTAC study. J Clin Oncol, 2012, 30: abstr 7522.Fujita Y, Suda K, Kimura H et al. Highly sensitive detection of EGFR T790M mutation using colony hybridization predicts favorable prognosis of patients with lung cancer harboring activating EGFR mutation. J Thorac Oncol, 2012, 7: 1640-1644.Fujita Y, Suda K, Kimura H et al. Highly sensitive detection of EGFR T790M mutation using colony hybridization predicts favorable prognosis of patients with lung cancer harboring activating EGFR mutation. J Thorac Oncol, 2012, 7: 1640-1644.Girard N, Lou E, Azzoli CG et al. Analysis of genetic variants in never-smokers with lung cancer facilitated by an Internet-based blood collection protocol: a preliminary report. Clin Cancer Res, 2010, 16: 755-763.Girard N, Lou E, Azzoli CG et al. Analysis of genetic variants in never-smokers with lung cancer facilitated by an Internet-based blood collection protocol: a preliminary report. Clin Cancer Res, 2010, 16: 755-763.Ikeda K, Nomori H, Mori T et al. Novel germline mutation: EGFR V843I in patient with multiple lung adenocarcinomas and family members with lung cancer. Ann Thorac Surg, 2008, 85: 1430-1432.Ikeda K, Nomori H, Mori T et al. Novel germline mutation: EGFR V843I in patient with multiple lung adenocarcinomas and family members with lung cancer. Ann Thorac Surg, 2008, 85: 1430-1432.Ohtsuka K, Ohnishi H, Kurai D et al. Familial lung adenocarcinoma caused by the EGFR V843I germline mutation. J Clin Oncol, 2011, 29: e191-192.Ohtsuka K, Ohnishi H, Kurai D et al. Familial lung adenocarcinoma caused by the EGFR V843I germline mutation. J Clin Oncol, 2011, 29: e191-192.Jackman D, Pao W, Reily GJ et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in nonsmall-cell lung cancer. J. Clin. Oncol., 2010, 28: 357-360.Jackman D, Pao W, Reily GJ et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in nonsmall-cell lung cancer. J. Clin. Oncol., 2010, 28: 357-360.Gandara DR, Lara PN et al. Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications. Clin. Lung Cancer, 2014, 15: 1-6.Gandara DR, Lara PN et al. Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications. Clin. Lung Cancer, 2014, 15: 1-6.Park K, Tsai C-M, Ahn M-J et al. ASPIRATION: Phase II study of continued erlotinib beyond RECIST progression in Asian patient (pts) with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). J. Clin. Oncol., 2012, 30: A#TPS7614.Park K, Tsai C-M, Ahn M-J et al. ASPIRATION: Phase II study of continued erlotinib beyond RECIST progression in Asian patient (pts) with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). J. Clin. Oncol., 2012, 30: A#TPS7614.Mok TS, Kim SW, Wu YL et al. Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive nonsmall-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analysis. J Clin Oncol, 2017 Oct 2. doi: 10.1200/JCO.2017.73.9250.Mok TS, Kim SW, Wu YL et al. Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive nonsmall-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analysis. J Clin Oncol, 2017 Oct 2. doi: 10.1200/JCO.2017.73.9250.Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med, 2010, 362: 2380-2388.Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med, 2010, 362: 2380-2388.Kobayashi S, Boggon TJ, Dayaram T et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med, 2005, 352: 786-792.Kobayashi S, Boggon TJ, Dayaram T et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med, 2005, 352: 786-792.Pao W, Miller VA, Politi KA 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: e73.Pao W, Miller VA, Politi KA 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: e73.Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene, 2009, 28: S24-31.Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene, 2009, 28: S24-31.Oxnard GR, Arcila ME, Chmielecki J et al. New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin Cancer Res, 2011, 17: 5530-5537.Oxnard GR, Arcila ME, Chmielecki J et al. New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin Cancer Res, 2011, 17: 5530-5537.Regales L, Gong Y, Shen R et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest, 2009, 119: 3000-3010.Regales L, Gong Y, Shen R et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest, 2009, 119: 3000-3010.Janjigian YY, Smit EF, Groen HJ et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov, 2014, 4: 1036-1045.Janjigian YY, Smit EF, Groen HJ et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov, 2014, 4: 1036-1045.Mok TS, Wu Y-L, Ahn M-J et al. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung. Cancer N Engl J Med, 2017, 376: 629-640.Mok TS, Wu Y-L, Ahn M-J et al. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung. Cancer N Engl J Med, 2017, 376: 629-640.Ramalingam S.S., Yang JC-H, Chee Khoon Lee. Osimertinib As First-Line Treatment of EGFR Mutation–Positive Advanced Non–Small-Cell Lung. Cancer J Clin Oncol, 35. Aug2017.Ramalingam S.S., Yang JC-H, Chee Khoon Lee. Osimertinib As First-Line Treatment of EGFR Mutation–Positive Advanced Non–Small-Cell Lung. Cancer J Clin Oncol, 35. Aug2017.Niederst MJ, Hu H, Mulvey HE et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res, 2015, 21: 3924-3933.Niederst MJ, Hu H, Mulvey HE et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res, 2015, 21: 3924-3933.Lovly CM. ASCO EDUCATIONAL BOOK, 2015: e165-173.Lovly CM. ASCO EDUCATIONAL BOOK, 2015: e165-173.Sequist LV, Waltman BA, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med, 2011, 3: 75ra26.Sequist LV, Waltman BA, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med, 2011, 3: 75ra26.Takezawa K, Pirazzoli V, Arcila ME et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFRmutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov, 2012, 2: 922-933.Takezawa K, Pirazzoli V, Arcila ME et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFRmutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov, 2012, 2: 922-933.Pao W, Wang TY, Riely GJ et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med, 2005, 2: e17.Pao W, Wang TY, Riely GJ et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med, 2005, 2: e17.Ohashi K, Sequist LV, Arcila ME et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A, 2012, 109: E2127-2133.Ohashi K, Sequist LV, Arcila ME et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A, 2012, 109: E2127-2133.Ercan D, Xu C, Yanagita M et al. Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. Cancer Discov, 2012, 2: 934-947.Ercan D, Xu C, Yanagita M et al. Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. Cancer Discov, 2012, 2: 934-947.Engelman JA, Mukohara T, Zejnullahu K et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFRamplified lung cancer. J Clin Invest, 2006, 116: 2695-2706.Engelman JA, Mukohara T, Zejnullahu K et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFRamplified lung cancer. J Clin Invest, 2006, 116: 2695-2706.Zhang Z, Lee JC, Lin L et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet, 2012, 44: 852-860.Zhang Z, Lee JC, Lin L et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet, 2012, 44: 852-860.Byers LA, Diao L, Wang J et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res, 2013, 19: 279-290.Byers LA, Diao L, Wang J et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res, 2013, 19: 279-290.Bivona TG, Hieronymus H, Parker J et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature, 2011, 471: 523-6KDM5A.Bivona TG, Hieronymus H, Parker J et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature, 2011, 471: 523-6KDM5A.Sharma SV, Lee DY, Li B et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell, 2010, 141: 69-80.Sharma SV, Lee DY, Li B et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell, 2010, 141: 69-80.Brock A, Chang H, Huang S. Non-genetic heterogeneity-a mutation-independent driving force for the somatic evolution of tumours. Nat Rev Genet, 2009, 10: 336-342.Brock A, Chang H, Huang S. Non-genetic heterogeneity-a mutation-independent driving force for the somatic evolution of tumours. Nat Rev Genet, 2009, 10: 336-342.Gupta PB, Fillmore CM, Jiang G et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell, 2011, 146: 633-644.Gupta PB, Fillmore CM, Jiang G et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell, 2011, 146: 633-644.Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2002, 2: 442-454. 46. Thomson S, Buck E, Petti F et al. 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: 9455-9462.Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2002, 2: 442-454. 46. Thomson S, Buck E, Petti F et al. 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: 9455-9462.Rho JK, Choi YJ, Lee JK et al. Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line. Lung Cancer, 2009, 63: 219-226.Rho JK, Choi YJ, Lee JK et al. Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line. Lung Cancer, 2009, 63: 219-226.Suda K, Tomizawa K, Fujii M et al. Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib. J Thorac Oncol, 2011, 6: 1152-1161.Suda K, Tomizawa K, Fujii M et al. Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib. J Thorac Oncol, 2011, 6: 1152-1161.Buonato JM, Lazzara MJ. ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition. Cancer Res, 2014, 74: 309-319.Buonato JM, Lazzara MJ. ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition. Cancer Res, 2014, 74: 309-319.Sequist LV, Waltman BA, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med, 2011, 3: 75ra26.Sequist LV, Waltman BA, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med, 2011, 3: 75ra26.

The authors declare that there are no conflicts of interest present.