SpringerLink
Log in

Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

  • Review
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

Abstract

The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9–13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Iragavarapu C, Mustafa M, Akinleye A, Furqan M, Mittal V, Cang S, Liu D. Novel ALK inhibitors in clinical use and development. J Hematol Oncol 2015; 8(1): 17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol 2016; 9(1): 34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. West H. Nivolumab as first line monotherapy for advanced non-small cell lung cancer: could we replace first line chemotherapy with immunotherapy? Transl Lung Cancer Res 2014; 3(6): 400–402

    PubMed  PubMed Central  Google Scholar 

  4. Wu J, Savooji J, Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol 2016; 9(1): 19

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R, Engen JR, Wong KK, Eck MJ, Gray NS, Jänne PA. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 2009; 462(7276): 1070–1074

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Park K, Tan EH, O’Byrne K, Zhang L, Boyer M, Mok T, Hirsh V, Yang JC, Lee KH, Lu S, Shi Y, Kim SW, Laskin J, Kim DW, Arvis CD, Kölbeck K, Laurie SA, Tsai CM, Shahidi M, Kim M, Massey D, Zazulina V, Paz-Ares L. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016; 17(5): 577–589

    Article  PubMed  CAS  Google Scholar 

  7. Chi A, Remick S, Tse W. EGFR inhibition in non-small cell lung cancer: current evidence and future directions. Biomark Res 2013; 1(1): 2

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, Lu S, Cheng Y, Han B, Chen L, Huang C, Qin S, Zhu Y, Pan H, Liang H, Li E, Jiang G, How SH, Fernando MC, Zhang Y, **a F, Zuo Y. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015; 26(9): 1883–1889

    Article  PubMed  Google Scholar 

  9. Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Lee DH, Liu Y, Yoh K, Zhou JY, Shi X, Webster A, Jiang H, Mok TS. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation- positive non-small-cell lung cancer after progression on firstline gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol 2015; 16(8): 990–998

    Article  PubMed  CAS  Google Scholar 

  10. Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O’Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015; 16(2): 141–151

    Article  PubMed  CAS  Google Scholar 

  11. Zhai H, Zhong W, Yang X, Wu YL. Neoadjuvant and adjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFRTKI) therapy for lung cancer. Transl Lung Cancer Res 2015; 4(1): 82–93

    PubMed  PubMed Central  CAS  Google Scholar 

  12. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, **u Q, Ma J, Zhang L, You C. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol 2015; 26(9): 1877–1883

    Article  PubMed  CAS  Google Scholar 

  13. Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Göker E, Georgoulias V, Li W, Isla D, Guclu SZ, Morabito A, Min YJ, Ardizzoni A, Gadgeel SM, Wang B, Chand VK, Goss GD; LU XLung. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015; 16(8): 897–907

    Article  PubMed  CAS  Google Scholar 

  14. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007; 7(3): 169–181

    Article  PubMed  CAS  Google Scholar 

  15. Niu FY, Wu YL. Novel agents and strategies for overcoming EGFR TKIs resistance. Exp Hematol Oncol 2014; 3(1): 2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Engel J, Richters A, Getlik M, Tomassi S, Keul M, Termathe M, Lategahn J, Becker C, Mayer-Wrangowski S, Grütter C, Uhlenbrock N, Krüll J, Schaumann N, Eppmann S, Kibies P, Hoffgaard F, Heil J, Menninger S, Ortiz-Cuaran S, Heuckmann JM, Tinnefeld V, Zahedi RP, Sos ML, Schultz-Fademrecht C, Thomas RK, Kast SM, Rauh D. Targeting drug resistance in EGFR with covalent inhibitors: a structure-based design approach. J Med Chem 2015; 58(17): 6844–6863

    Article  PubMed  CAS  Google Scholar 

  17. Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, ** H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim DW, Ranson MR, Pao W. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014; 4(9): 1046–1061

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Park KLJS, Lee KH, Kim JH, Min YJ, Cho JY, Han JY, Kim BS, Kim JS, Lee DH, Kang JH, Cho EK, Jang IJ. Jung J, Kim H-Y, Sin HJ, Son J, Woo JS, Kim D-W Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI). ASCO Meeting Abstracts 2015;33(15_suppl):8084

    Google Scholar 

  19. Sequist LV, Rolfe L, Allen AR. Rociletinib in EGFR-mutated nonsmall- cell lung cancer. N Engl J Med 2015; 373(6): 578–579

    Article  PubMed  CAS  Google Scholar 

  20. Walter AO, S** RT, Haringsma HJ, Ohashi K, Sun J, Lee K, Dubrovskiy A, Labenski M, Zhu Z, Wang Z, Sheets M, St Martin T, Karp R, van Kalken D, Chaturvedi P, Niu D, Nacht M, Petter RC, Westlin W, Lin K, Jaw-Tsai S, Raponi M, Van Dyke T, Etter J, Weaver Z, Pao W, Singh J, Simmons AD, Harding TC, Allen A. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov 2013; 3(12): 1404–1415

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, Padera RF, Shapiro GI, Baum A, Himmelsbach F, Rettig WJ, Meyerson M, Solca F, Greulich H, Wong KK. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27(34): 4702–4711

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Planchard D, Loriot Y, André F, Gobert A, Auger N, Lacroix L, Soria JC. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol 2015; 26(10): 2073–2078

    Article  PubMed  CAS  Google Scholar 

  23. Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, Ercan D, Matthews SE, Cantarini M, Barrett JC, Jänne PA, Oxnard GR. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med 2015; 21(6): 560–562

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Niederst MJ, Hu H, Mulvey HE, Lockerman EL, Garcia AR, Piotrowska Z, Sequist LV, Engelman JA. 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(17): 3924–3933

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Yu HA, Tian SK, Drilon AE, Borsu L, Riely GJ, Arcila ME, Ladanyi M. Acquired resistance of EGFR-mutant lung cancer to a T790 Mspecific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain. JAMA Oncol 2015; 1(7): 982–984

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wang S, Tsui ST, Liu C, Song Y, Liu D. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer. J Hematol Oncol 2016; 9(1): 59

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Song HN, Jung KS, Yoo KH, Cho J, Lee JY, Lim SH, Kim HS, Sun JM, Lee SH, Ahn JS, Park K, Choi YL, Park W, Ahn MJ. Acquired C797S mutation upon treatment with a T790M-specific thirdgeneration EGFR inhibitor (HM61713) in non-small cell lung cancer. J Thorac Oncol 2016; 11(4): e45–e47

    Article  PubMed  Google Scholar 

  28. Ercan D, Choi HG, Yun CH, Capelletti M, **e T, Eck MJ, Gray NS, Jänne PA. EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clin Cancer Res 2015; 21(17): 3913–3923

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Bersanelli M, Minari R, Bordi P, Gnetti L, Bozzetti C, Squadrilli A, Lagrasta CA, Bottarelli L, Osipova G, Capelletto E, Mor M, Tiseo M. L718Q mutation as new mechanism of acquired resistance to AZD9291 in EGFR-mutated NSCLC. J Thorac Oncol 2016; 11(10): e121–123

    Article  PubMed  Google Scholar 

  30. Ortiz-Cuaran S, Scheffler M, Plenker D, Dahmen L, Scheel AH, Fernandez-Cuesta L, Meder L, Lovly CM, Persigehl T, Merkelbach-Bruse S, Bos M, Michels S, Fischer R, Albus K, König K, Schildhaus HU, Fassunke J, Ihle MA, Pasternack H, Heydt C, Becker C, Altmüller J, Ji H, Müller C, Florin A, Heuckmann JM, Nuernberg P, Ansén S, Heukamp LC, Berg J, Pao W, Peifer M, Buettner R, Wolf J, Thomas RK, Sos ML. Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors. Clin Cancer Res 2016; 22(19): 4837–4847

    Article  PubMed  CAS  Google Scholar 

  31. Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, Xu C, Rhee K, Chen T, Zhang H, Palakurthi S, Jang J, Lelais G, Di Donato M, Bursulaya B, Michellys PY, Epple R, Marsilje TH, McNeill M, Lu W, Harris J, Bender S, Wong KK, Jänne PA, Eck MJ. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 2016; 534(7605): 129–132

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Brevet M, Johnson ML, Azzoli CG, Ladanyi M. Detection of EGFR mutations in plasma DNA from lung cancer patients by mass spectrometry genoty** is predictive of tumor EGFR status and response to EGFR inhibitors. Lung Cancer 2011; 73(1): 96–102

    Article  PubMed  Google Scholar 

  33. Luo J, Shen L, Zheng D. Diagnostic value of circulating free DNA for the detection of EGFR mutation status in NSCLC: a systematic review and meta-analysis. Sci Rep 2014; 4: 6269

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Ma M, Shi C, Qian J, Teng J, Zhong H, Han B. Comparison of plasma and tissue samples in epidermal growth factor receptor mutation by ARMS in advanced non-small cell lung cancer. Gene 2016; 591(1): 58–64

    Article  PubMed  CAS  Google Scholar 

  35. Matikas A, Syrigos KN, Agelaki S. Circulating biomarkers in nonsmall-cell lung cancer: current status and future challenges. Clin Lung Cancer 2016 Jun 8. [Epub ahead of print] doi:10.1016/j.cllc.2016.1005.1021

    Google Scholar 

  36. Sun W, Yuan X, Tian Y, Wu H, Xu H, Hu G, Wu K. Non-invasive approaches to monitor EGFR-TKI treatment in non-small-cell lung cancer. J Hematol Oncol 2015; 8(1): 95

    Article  PubMed  PubMed Central  Google Scholar 

  37. Wu Y, Liu H, Shi X, Song Y. Can EGFR mutations in plasma or serum be predictive markers of non-small-cell lung cancer? A metaanalysis. Lung Cancer 2015; 88(3): 246–253

    Article  PubMed  Google Scholar 

  38. Cang S, Iragavarapu C, Savooji J, Song Y, Liu D. ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J Hematol Oncol 2015; 8(1): 129

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435(7042): 677–681

    Article  PubMed  CAS  Google Scholar 

  40. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, ** S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, **ao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013; 19(2): 202–208

    Article  PubMed  CAS  Google Scholar 

  41. Tsujimoto Y, Shimizu S. Bcl-2 family: life-or-death switch. FEBS Lett 2000; 466(1): 6–10

    Article  PubMed  CAS  Google Scholar 

  42. Das A, Wei G, Parikh K, Liu D. Selective inhibitors of nuclear export (SINE) in hematological malignancies. Exp Hematol Oncol 2015; 4(1): 7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Gravina GL, Senapedis W, McCauley D, Baloglu E, Shacham S, Festuccia C. Nucleo-cytoplasmic transport as a therapeutic target of cancer. J Hematol Oncol 2014; 7(1): 85

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Gravina GL, Tortoreto M, Mancini A, Addis A, Di Cesare E, Lenzi A, Landesman Y, McCauley D, Kauffman M, Shacham S, Zaffaroni N, Festuccia C. XPO1/CRM1-selective inhibitors of nuclear export (SINE) reduce tumor spreading and improve overall survival in preclinical models of prostate cancer (PCa). J Hematol Oncol 2014; 7(1): 46

    Article  PubMed  PubMed Central  Google Scholar 

  45. Parikh K, Cang S, Sekhri A, Liu D. Selective inhibitors of nuclear export (SINE)—a novel class of anti-cancer agents. J Hematol Oncol 2014; 7(1): 78

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Naidu S, Magee P, Garofalo M. miRNA-based therapeutic intervention of cancer. J Hematol Oncol 2015; 8(1): 68

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Sanchez-Mejias A, Tay Y. Competing endogenous RNA networks: tying the essential knots for cancer biology and therapeutics. J Hematol Oncol 2015; 8(1): 30

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Alexander PB, Wang XF. Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies. Front Med 2015; 9(2): 134–138

    Article  PubMed  PubMed Central  Google Scholar 

  49. Cho J, Chen L, Sangji N, Okabe T, Yonesaka K, Francis JM, Flavin RJ, Johnson W, Kwon J, Yu S, Greulich H, Johnson BE, Eck MJ, Jänne PA, Wong KK, Meyerson M. Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization. Cancer Res 2013; 73(22): 6770–6779

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373(2): 123–135

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373(17): 1627–1639

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Davar D, Socinski MA, Dacic S, Burns TF. Near complete response after single dose of nivolumab in patient with advanced heavily pretreated KRAS mutant pulmonary adenocarcinoma. Exp Hematol Oncol 2015; 4(1): 34

    Article  PubMed  PubMed Central  Google Scholar 

  53. Schuller AG, Barry ER, Jones RD, Henry RE, Frigault MM, Beran G, Linsenmayer D, Hattersley M, Smith A, Wilson J, Cairo S, Déas O, Nicolle D, Adam A, Zinda M, Reimer C, Fawell SE, Clark EA, D’Cruz CM. The MET inhibitor AZD6094 (savolitinib, HMPL-504) induces regression in papillary renal cell carcinoma patientderived xenograft models. Clin Cancer Res 2015; 21(12): 2811–2819

    Article  PubMed  CAS  Google Scholar 

  54. Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, Pentlow KS, Zanzonico PB, Haque S, Gavane S, Ghossein RA, Ricarte-Filho JC, Domínguez JM, Shen R, Tuttle RM, Larson SM, Fagin JA. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013; 368(7): 623–632

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Smith AD, Roda D, Yap TA. Strategies for modern biomarker and drug development in oncology. J Hematol Oncol 2014; 7(1): 70

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Zhong W, Yang X, Yan H, Zhang X, Su J, Chen Z, Liao R, Nie Q, Dong S, Zhou Q, Yang J, Tu H, Wu YL. Phase II study of biomarker-guided neoadjuvant treatment strategy for IIIA-N2 nonsmall cell lung cancer based on epidermal growth factor receptor mutation status. J Hematol Oncol 2015; 8(1): 54

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013; 8(7): 823–859

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Sun Z, Chen X, Wang G, Li L, Fu G, Kuruc M, Wang X. Identification of functional metabolic biomarkers from lung cancer patient serum using PEP technology. Biomark Res 2016; 4(1): 11

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Bei**g, 100142, China

    Shuhang Wang & Feifei Yan

  2. Henan Cancer Hospital and the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, China

    Yong** Song & Delong Liu

Authors
  1. Shuhang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yong** Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feifei Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Delong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Delong Liu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, S., Song, Y., Yan, F. et al. Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors. Front. Med. 10, 383–388 (2016). https://doi.org/10.1007/s11684-016-0488-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-016-0488-1

Keywords

Search

Navigation