Drug Resistance to EGFR Inhibitors in Lung Cancer

Background: The discovery of mutations in epidermal growth factor receptor (EGFR) has dramatically changed the treatment of patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths worldwide. EGFR-targeted therapies show considerable promise, but drug resistance has become a substantial issue. Methods: We reviewed the literature to provide an overview of the drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Results: The mechanisms causing primary, acquired and persistent drug resistance to TKIs vary. Researchers and clinicians, who have used study findings to develop more effective therapeutic approaches, have found that the sequential use of single agents presents a formidable challenge, suggesting that multidrug combinations must be considered. Conclusions: In the era of precision medicine, oncologists should promptly obtain an accurate diagnosis of drug resistance in each patient to be able to design the most relevant combination therapy to overcome patient-specific drug resistance.

[1]  F. McCormick,et al.  ETS1 inactivation causes innate drug resistance to EGFR inhibitors , 2016, Molecular & cellular oncology.

[2]  P. Jänne,et al.  Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib , 2016, Oncogene.

[3]  Frank McCormick,et al.  AKT inactivation causes persistent drug tolerance to EGFR inhibitors. , 2015, Pharmacological research.

[4]  S. Ramaswamy,et al.  Mechanisms of Cancer Cell Dormancy--Another Hallmark of Cancer? , 2015, Cancer research.

[5]  G. Veronesi,et al.  When is surgery indicated for small-cell lung cancer? , 2015, Lung cancer.

[6]  F. McCormick,et al.  EGFR inhibition generates drug-tolerant persister cells by blocking AKT activity , 2015 .

[7]  S. Oh,et al.  Comparison of the Efficacy between Pemetrexed plus Platinum and Non-Pemetrexed plus Platinum as First-Line Treatment in Patients with Wild-Type Epidermal Growth Factor Receptor Nonsquamous Non-Small Cell Lung Cancer: A Retrospective Analysis , 2015, Chemotherapy.

[8]  G. Giaccone,et al.  Refining the treatment of NSCLC according to histological and molecular subtypes , 2015, Nature Reviews Clinical Oncology.

[9]  F. McCormick,et al.  Resistance to EGFR-targeted therapy by Ets-1 inactivation , 2015, Cell cycle.

[10]  D. Planchard,et al.  EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  K. Politi,et al.  Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer , 2015, Clinical Cancer Research.

[12]  G. Scagliotti,et al.  Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-Cell Lung Cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Martin Vingron,et al.  Comprehensive genomic profiles of small cell lung cancer , 2015, Nature.

[14]  F. McCormick,et al.  EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function , 2015, Proceedings of the National Academy of Sciences.

[15]  W. Pao,et al.  Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models. , 2015, Cancer research.

[16]  P. Jänne,et al.  Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer. , 2015, Cancer discovery.

[17]  M. Nishio,et al.  Phase I study of the HER3-targeted antibody patritumab (U3-1287) combined with erlotinib in Japanese patients with non-small cell lung cancer. , 2015, Lung cancer.

[18]  P. Jänne,et al.  EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors , 2015, Clinical Cancer Research.

[19]  S. Laufer,et al.  Fighting cancer drug resistance: Opportunities and challenges for mutation-specific EGFR inhibitors. , 2015, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[20]  S. Digumarthy,et al.  Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor. , 2015, Cancer discovery.

[21]  P. Jänne,et al.  AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. , 2015, The New England journal of medicine.

[22]  J. Neal,et al.  Rociletinib in EGFR-mutated non-small-cell lung cancer. , 2015, The New England journal of medicine.

[23]  Aleksandra Markovets,et al.  Acquired EGFR C797S mediates resistance to AZD9291 in advanced non-small cell lung cancer harboring EGFR T790M , 2015, Nature Medicine.

[24]  L. Sequist,et al.  Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. , 2015, The Lancet. Oncology.

[25]  Shu-Min Lin,et al.  Overall Response to First-Line Tyrosine Kinase Inhibitor and Second-Line Chemotherapy Is Predictive of Survival Outcome in Epidermal Growth Factor Receptor-Mutated Adenocarcinoma , 2015, Chemotherapy.

[26]  G. Getz,et al.  RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer , 2015, Nature Communications.

[27]  F. Collins,et al.  A new initiative on precision medicine. , 2015, The New England journal of medicine.

[28]  M. Stockler,et al.  Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial. , 2014, The Lancet. Oncology.

[29]  P. Jänne,et al.  Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas , 2014, European Respiratory Review.

[30]  P. Bragado,et al.  Mechanisms of disseminated cancer cell dormancy: an awakening field , 2014, Nature Reviews Cancer.

[31]  W. Pao,et al.  Acquired resistance to TKIs in solid tumours: learning from lung cancer , 2014, Nature Reviews Clinical Oncology.

[32]  Steven J. M. Jones,et al.  Comprehensive molecular profiling of lung adenocarcinoma , 2014, Nature.

[33]  William Pao,et al.  AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. , 2014, Cancer discovery.

[34]  O. Maertens,et al.  Paths of resistance to EGFR inhibitors: is NF enough? , 2014, Cancer discovery.

[35]  R. Bernards,et al.  Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. , 2014, Cancer discovery.

[36]  Ying Zhang.  Persisters, persistent infections and the Yin–Yang model , 2014, Emerging Microbes & Infections.

[37]  P. Jänne,et al.  The quest to overcome resistance to EGFR-targeted therapies in cancer , 2013, Nature Medicine.

[38]  Juswinder Singh,et al.  Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. , 2013, Cancer discovery.

[39]  G. Giaccone,et al.  Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. , 2013, The Lancet. Oncology.

[40]  T. Ohira,et al.  Insulin-like growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine kinase inhibitor gefitinib in non-small cell lung cancer , 2013, Cellular Oncology.

[41]  K. Kinzler,et al.  Cancer Genome Landscapes , 2013, Science.

[42]  T. Betsuyaku,et al.  Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC , 2013, Molecular Cancer Research.

[43]  William Pao,et al.  Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  P. Jänne,et al.  New targetable oncogenes in non-small-cell lung cancer. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  William Pao,et al.  Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers , 2013, Clinical Cancer Research.

[46]  Katherine R. Singleton,et al.  A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop , 2013, Oncogenesis.

[47]  Marc Ladanyi,et al.  EGFR Exon 20 Insertion Mutations in Lung Adenocarcinomas: Prevalence, Molecular Heterogeneity, and Clinicopathologic Characteristics , 2013, Molecular Cancer Therapeutics.

[48]  Shan-Mei Xu,et al.  Alveolar Type II Cells Possess the Capability of Initiating Lung Tumor Development , 2012, PloS one.

[49]  M. Ladanyi,et al.  HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. , 2012, Cancer discovery.

[50]  William Pao,et al.  Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1 , 2012, Proceedings of the National Academy of Sciences.

[51]  Jane Fridlyand,et al.  Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors , 2012, Nature.

[52]  T. Golub,et al.  Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion , 2012, Nature.

[53]  Jae Cheol Lee,et al.  Activation of the AXL Kinase Causes Resistance to EGFR-Targeted Therapy in Lung Cancer , 2012, Nature Genetics.

[54]  Andrew L. Kung,et al.  Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia , 2012, Nature Medicine.

[55]  Yan Sun,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. , 2012, The Lancet. Oncology.

[56]  Jun-ling Liu,et al.  Activation of notch‐1 enhances epithelial–mesenchymal transition in gefitinib‐acquired resistant lung cancer cells , 2012, Journal of cellular biochemistry.

[57]  F. Hirsch,et al.  Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  M. Nöthen,et al.  A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer , 2012, Nature Medicine.

[59]  Mari Mino-Kenudson,et al.  EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. , 2012, Cancer discovery.

[60]  E. Felip,et al.  Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. , 2012, The Lancet. Oncology.

[61]  Y. Miyagi,et al.  WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors , 2012, Laboratory Investigation.

[62]  Sung-Liang Yu,et al.  Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  H. Uramoto,et al.  Expression of selected gene for acquired drug resistance to EGFR-TKI in lung adenocarcinoma. , 2011, Lung cancer.

[64]  H. Hieronymus,et al.  FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR , 2011, Nature.

[65]  S. Digumarthy,et al.  Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors , 2011, Science Translational Medicine.

[66]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[67]  N. Girard,et al.  New driver mutations in non-small-cell lung cancer. , 2011, The Lancet. Oncology.

[68]  Rie Kondo,et al.  Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis , 2011, BMC Cancer.

[69]  William Pao,et al.  Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer , 2010, Nature Reviews Cancer.

[70]  H. Uramoto,et al.  Cancer esearch apeutics , Targets , and Chemical Biology s of PTEN Expression by Blocking Nuclear Translocation GR 1 in Gefitinib-Resistant Lung Cancer Cells Harboring R ermal Growth Factor Receptor – Activating Mutations , 2010 .

[71]  Young Lim Choi,et al.  EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. , 2010, The New England journal of medicine.

[72]  N. Altorki,et al.  TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer , 2010, Proceedings of the National Academy of Sciences.

[73]  Susan Quinn,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. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[74]  E. Felip,et al.  Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[75]  P. Jänne,et al.  Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor , 2010, Oncogene.

[76]  Ben S. Wittner,et al.  A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations , 2010, Cell.

[77]  M. Kris,et al.  Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[78]  J. Neal.  Histology Matters: Individualizing Treatment in Non-Small Cell Lung Cancer , 2010, The oncologist.

[79]  A. Gazdar,et al.  Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors , 2009, Oncogene.

[80]  S. Kobayashi,et al.  Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. , 2009, Clinical lung cancer.

[81]  Raghu Kalluri,et al.  The basics of epithelial-mesenchymal transition. , 2009, The Journal of clinical investigation.

[82]  L. Crinò,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. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[83]  M. Meyerson,et al.  PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. , 2009, Cancer research.

[84]  M. Ladanyi,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 , 2008, Clinical Cancer Research.

[85]  John Kuriyan,et al.  Activation of tyrosine kinases by mutation of the gatekeeper threonine , 2008, Nature Structural &Molecular Biology.

[86]  M. Ladanyi,et al.  Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma , 2008, Clinical Cancer Research.

[87]  Kikuya Kato,et al.  Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib , 2008, Cancer science.

[88]  M. Meyerson,et al.  The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP , 2008, Proceedings of the National Academy of Sciences.

[89]  M. Meyerson,et al.  PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. , 2007, Cancer research.

[90]  William Pao,et al.  MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib , 2007, Proceedings of the National Academy of Sciences.

[91]  J. Aguirre-Ghiso,et al.  Models, mechanisms and clinical evidence for cancer dormancy , 2007, Nature Reviews Cancer.

[92]  A. Strasser,et al.  Gefitinib-Induced Killing of NSCLC Cell Lines Expressing Mutant EGFR Requires BIM and Can Be Enhanced by BH3 Mimetics , 2007, PLoS medicine.

[93]  D. Tenen,et al.  BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations , 2007, PLoS medicine.

[94]  W. Pao,et al.  Induction of BIM Is Essential for Apoptosis Triggered by EGFR Kinase Inhibitors in Mutant EGFR-Dependent Lung Adenocarcinomas , 2007, PLoS medicine.

[95]  Joon-Oh Park,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2007, Science.

[96]  Roy S Herbst,et al.  KRAS Mutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer , 2007, Clinical Cancer Research.

[97]  Daniel A. Haber,et al.  Epidermal growth factor receptor mutations in lung cancer , 2007, Nature Reviews Cancer.

[98]  J. D. de Bono,et al.  Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2 (HER2/neu). , 2007, European journal of cancer.

[99]  William Pao,et al.  Novel D761Y and Common Secondary T790M Mutations in Epidermal Growth Factor Receptor–Mutant Lung Adenocarcinomas with Acquired Resistance to Kinase Inhibitors , 2006, Clinical Cancer Research.

[100]  Nobuyoshi Shimizu,et al.  Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. , 2006, Cancer research.

[101]  P. Jänne,et al.  Effect of Epidermal Growth Factor Receptor Tyrosine Kinase Domain Mutations on the Outcome of Patients with Non–Small Cell Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors , 2006, Clinical Cancer Research.

[102]  M. Ladanyi,et al.  EGFR mutations in small-cell lung cancers in patients who have never smoked. , 2006, The New England journal of medicine.

[103]  J. Minna,et al.  Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. , 2006, Cancer cell.

[104]  F. Cappuzzo,et al.  Insulin-like growth factor receptor 1 (IGFR-1) is significantly associated with longer survival in non-small-cell lung cancer patients treated with gefitinib. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[105]  R. Pazdur,et al.  FDA drug approval summary: erlotinib (Tarceva) tablets. , 2005, The oncologist.

[106]  Renato Martins,et al.  Erlotinib in previously treated non-small-cell lung cancer. , 2005, The New England journal of medicine.

[107]  Patricia L. Harris,et al.  Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[108]  H. Varmus,et al.  Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain , 2005, PLoS medicine.

[109]  Angela Greco,et al.  A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. , 2004, Gastroenterology.

[110]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[111]  Ramaswamy Nilakantan,et al.  Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase , 2004, Cancer Research.

[112]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[113]  J. Kern,et al.  Autocrine activation of ErbB2/ErbB3 receptor complex by NRG-1 in non-small cell lung cancer cell lines. , 2004, Lung cancer.

[114]  D. Felsher.  Reversibility of oncogene-induced cancer. , 2004, Current opinion in genetics & development.

[115]  Y. Yarden.  The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. , 2001, European journal of cancer.

[116]  P. N. Rao,et al.  Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification , 2001, Science.

[117]  José Luis de la Pompa,et al.  Negative Regulation of PKB/Akt-Dependent Cell Survival by the Tumor Suppressor PTEN , 1998, Cell.

[118]  L. Pustilnik,et al.  Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. , 1997, Cancer research.

[119]  H. Kim,et al.  Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (HER3) receptor protein. , 1997, The Biochemical journal.

[120]  Y. Yarden,et al.  A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor , 1996, Molecular and cellular biology.

[121]  A. Ullrich,et al.  Heregulin‐dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. , 1995, The EMBO journal.

[122]  J. Dufour,et al.  Cell lines , 2012, Spermatogenesis.

[123]  F. McCormick,et al.  Differential regulation of rasGAP and neurofibromatosis gene product activities , 1991, Nature.

[124]  J. Bigger.  TREATMENT OF STAPHYLOCOCCAL INFECTIONS WITH PENICILLIN BY INTERMITTENT STERILISATION , 1944 .

[125]  G. Hobby,et al.  Observations on the Mechanism of Action of Penicillin.∗ , 1942 .

[126]  J-L Pretet,et al.  Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[127]  T. Ohira,et al.  Insulin-like growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine kinase inhibitor gefitinib in non-small cell lung cancer , 2013, Cellular Oncology.

[128]  J. Baselga,et al.  ZD1839 (‘Iressa’)1,2 as an Anticancer Agent , 2012, Drugs.

[129]  M. Ladanyi,et al.  HER 2 Amplifi cation : A Potential Mechanism of Acquired Resistance to EGFR Inhibition in EGFR-Mutant Lung Cancers That Lack the Second-Site EGFR T 790 M Mutation , 2012 .

[130]  X. Teng,et al.  [Molecular pathology of lung cancer: key to personalized medicine]. , 2012, Zhonghua bing li xue za zhi = Chinese journal of pathology.

[131]  N. Hanna.  Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers , 2006 .

[132]  犬飼 道雄.  Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer , 2006 .

[133]  J. Baselga,et al.  ZD1839 ('Iressa') as an anticancer agent. , 2000, Drugs.