Frontiers of Medicine

, Volume 10, Issue 4, pp 383–388 | Cite as

Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

  • Shuhang Wang
  • Yongping Song
  • Feifei Yan
  • Delong Liu
Review

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.

Keywords

EGFR tyrosine kinase inhibitor AZD9291 EAI045 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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): 17CrossRefPubMedPubMedCentralGoogle Scholar
  2. 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): 34CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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): 400–402PubMedPubMedCentralGoogle Scholar
  4. 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): 19CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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): 1070–1074CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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): 577–589CrossRefPubMedGoogle Scholar
  7. 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): 2CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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, Xia 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): 1883–1889CrossRefPubMedGoogle Scholar
  9. 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): 990–998CrossRefPubMedGoogle Scholar
  10. 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): 141–151CrossRefPubMedGoogle Scholar
  11. 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): 82–93PubMedPubMedCentralGoogle Scholar
  12. 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, Xiu 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): 1877–1883CrossRefPubMedGoogle Scholar
  13. 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): 897–907CrossRefPubMedGoogle Scholar
  14. 14.
    Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007; 7(3): 169–181CrossRefPubMedGoogle Scholar
  15. 15.
    Niu FY, Wu YL. Novel agents and strategies for overcoming EGFR TKIs resistance. Exp Hematol Oncol 2014; 3(1): 2CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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): 6844–6863CrossRefPubMedGoogle Scholar
  17. 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, Jin 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): 1046–1061CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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):8084Google Scholar
  19. 19.
    Sequist LV, Rolfe L, Allen AR. Rociletinib in EGFR-mutated nonsmall- cell lung cancer. N Engl J Med 2015; 373(6): 578–579CrossRefPubMedGoogle Scholar
  20. 20.
    Walter AO, Sjin 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): 1404–1415CrossRefPubMedPubMedCentralGoogle Scholar
  21. 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): 4702–4711CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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): 2073–2078CrossRefPubMedGoogle Scholar
  23. 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): 560–562CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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): 3924–3933CrossRefPubMedPubMedCentralGoogle Scholar
  25. 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): 982–984CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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): 59CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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–e47CrossRefPubMedGoogle Scholar
  28. 28.
    Ercan D, Choi HG, Yun CH, Capelletti M, Xie T, Eck MJ, Gray NS, Jänne PA. EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clin Cancer Res 2015; 21(17): 3913–3923CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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): e121–123CrossRefPubMedGoogle Scholar
  30. 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): 4837–4847CrossRefPubMedGoogle Scholar
  31. 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): 129–132CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Brevet M, Johnson ML, Azzoli CG, Ladanyi M. Detection of EGFR mutations in plasma DNA from lung cancer patients by mass spectrometry genotyping is predictive of tumor EGFR status and response to EGFR inhibitors. Lung Cancer 2011; 73(1): 96–102CrossRefPubMedGoogle Scholar
  33. 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: 6269CrossRefPubMedPubMedCentralGoogle Scholar
  34. 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): 58–64CrossRefPubMedGoogle Scholar
  35. 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.2016.1005.1021Google Scholar
  36. 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): 95CrossRefPubMedPubMedCentralGoogle Scholar
  37. 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): 246–253CrossRefPubMedGoogle Scholar
  38. 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): 129CrossRefPubMedPubMedCentralGoogle Scholar
  39. 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): 677–681CrossRefPubMedGoogle Scholar
  40. 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, Jin 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, Xiao 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): 202–208CrossRefPubMedGoogle Scholar
  41. 41.
    Tsujimoto Y, Shimizu S. Bcl-2 family: life-or-death switch. FEBS Lett 2000; 466(1): 6–10CrossRefPubMedGoogle Scholar
  42. 42.
    Das A, Wei G, Parikh K, Liu D. Selective inhibitors of nuclear export (SINE) in hematological malignancies. Exp Hematol Oncol 2015; 4(1): 7CrossRefPubMedPubMedCentralGoogle Scholar
  43. 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): 85CrossRefPubMedPubMedCentralGoogle Scholar
  44. 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): 46CrossRefPubMedPubMedCentralGoogle Scholar
  45. 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): 78CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Naidu S, Magee P, Garofalo M. miRNA-based therapeutic intervention of cancer. J Hematol Oncol 2015; 8(1): 68CrossRefPubMedPubMedCentralGoogle Scholar
  47. 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): 30CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Alexander PB, Wang XF. Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies. Front Med 2015; 9(2): 134–138CrossRefPubMedPubMedCentralGoogle Scholar
  49. 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): 6770–6779CrossRefPubMedPubMedCentralGoogle Scholar
  50. 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): 123–135CrossRefPubMedPubMedCentralGoogle Scholar
  51. 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): 1627–1639CrossRefPubMedPubMedCentralGoogle Scholar
  52. 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): 34CrossRefPubMedPubMedCentralGoogle Scholar
  53. 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): 2811–2819CrossRefPubMedGoogle Scholar
  54. 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): 623–632CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Smith AD, Roda D, Yap TA. Strategies for modern biomarker and drug development in oncology. J Hematol Oncol 2014; 7(1): 70CrossRefPubMedPubMedCentralGoogle Scholar
  56. 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): 54CrossRefPubMedPubMedCentralGoogle Scholar
  57. 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): 823–859CrossRefPubMedPubMedCentralGoogle Scholar
  58. 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): 11CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Shuhang Wang
    • 1
  • Yongping Song
    • 2
  • Feifei Yan
    • 1
  • Delong Liu
    • 2
  1. 1.The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer HospitalBeijingChina
  2. 2.Henan Cancer Hospital and the Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina

Personalised recommendations