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Progress on treatment of MET signaling pathway in non-small cell lung cancer

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Abstract

MET activation includes gene mutation, amplification, and protein overexpression. Clinical evidence suggests that MET activation is both a primary oncogenic driver in lung cancer, and a secondary driver after acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Several small molecule TKIs have already shown to be effective in the MET pathway. However, the activation form and the diagnostic criteria of MET oncogene are still controversial, especially in patients resistant to EGFR TKIs or ALK TKIs. With the development of new MET inhibitors, a quantity of emerging trials has focused on the mechanism of acquired resistance to MET TKIs and therapeutic strategies after resistance.

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References

  1. Engelman JA, Kreshnik Z, Tetsuya M et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316(5827):1039–1043

    Article  CAS  PubMed  Google Scholar 

  2. James B, Cameron B, Jin-Yuan S et al (2007) MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 104(52):20932–20937

    Article  Google Scholar 

  3. Lawrence RE, Salgia R (2010) MET molecular mechanisms and therapies in lung cancer. Cell Adh Migr 4(1):146–152

    Article  PubMed  PubMed Central  Google Scholar 

  4. Garret S, Dhirendra G (2015) Gene of the month: MET. J Clin Pathol 68(6):405–409

    Article  Google Scholar 

  5. Shawna Leslie O, Ming-Sound T (2011) An overview of the c-MET signaling pathway. Ther Adv Med Oncol 3(1 Suppl):S7

    Google Scholar 

  6. Drilon A, Cappuzzo F, Ignatius Ou SH et al (2016) Targeting MET in lung cancer: will expectations finally be MET? J Thorac Oncol 12(1):S1556086416311790

    Google Scholar 

  7. Wu YL, Soo RA, Locatelli G et al (2017) Does c-Met remain a rational target for therapy in patients with EGFR TKI-resistant non-small cell lung cancer? Cancer Treat Rev 61:70–81. https://doi.org/10.1016/j.ctrv.2017.10.003

    Article  CAS  PubMed  Google Scholar 

  8. Guo R, Berry LD, Aisner DL et al (2019) MET IHC is a poor screen for MET amplification or MET exon 14 mutations in lung adenocarcinomas: data from a tri-institutional cohort of the lung cancer mutation consortium. J Thorac Oncol 14(9):1666–1671. https://doi.org/10.1016/j.jtho.2019.06.009

    Article  CAS  PubMed  Google Scholar 

  9. Wang Q, Yang S, Wang K et al (2019) MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer. 12 (1)

  10. Sanghui P, Yoon-La C, Ok SC et al (2012) High MET copy number and MET overexpression: poor outcome in non-small cell lung cancer patients. Histol Histopathol 27(2):197–207

    Google Scholar 

  11. Dimou A, Non L, Chae YK et al (2014) MET gene copy number predicts worse overall survival in patients with non-small cell lung cancer (NSCLC); a systematic review and meta-analysis. PLoS ONE 9(9):e107677

    Article  PubMed  PubMed Central  Google Scholar 

  12. Noonan SA, Berry L, Lu X et al (2016) Identifying the appropriate FISH criteria for defining MET copy number-driven lung adenocarcinoma through oncogene overlap analysis. J Thorac Oncol 11(8):1293–1304. https://doi.org/10.1016/j.jtho.2016.04.033

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tanaka A, Sueoka-Aragane N, Nakamura T et al (2012) Co-existence of positive MET FISH status with EGFR mutations signifies poor prognosis in lung adenocarcinoma patients. Lung Cancer 75(1):89–94. https://doi.org/10.1016/j.lungcan.2011.06.004

    Article  PubMed  Google Scholar 

  14. Kepinski-Lecomte C, Ergeç R (1998) Les céramiques de la prospection de Tilbeshar au Bronze ancien et Bronze moyen. Anatolia Antiqua 6(1):155–172

    Article  Google Scholar 

  15. Schrock AB, Frampton GM, Suh J et al (2016) Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations. J Thorac Oncol 11(9):1493–1502. https://doi.org/10.1016/j.jtho.2016.06.004

    Article  PubMed  Google Scholar 

  16. Reungwetwattana T, Liang Y, Zhu V et al (2017) The race to target MET exon 14 skipping alterations in non-small cell lung cancer: the why, the how, the who, the unknown, and the inevitable. Lung Cancer 103:27–37

    Article  PubMed  Google Scholar 

  17. Liu SY, Gou LY, Li AN et al (2016) The unique characteristics of MET exon 14 mutation in Chinese patients with NSCLC. J Thorac Oncol 11(9):1503–1510. https://doi.org/10.1016/j.jtho.2016.05.016

    Article  PubMed  Google Scholar 

  18. Kong-Beltran M, Seshagiri S, Zha J et al (2006) Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res 66(1):283–289. https://doi.org/10.1158/0008-5472.CAN-05-2749

    Article  CAS  PubMed  Google Scholar 

  19. Tong JH, Yeung SF, Chan AW et al (2016) MET amplification and exon 14 splice site mutation define unique molecular subgroups of Non-small Cell Lung Carcinoma with poor prognosis. Clin Cancer Res 22(12):3048

    Article  CAS  PubMed  Google Scholar 

  20. Paik PK, Drilon A, Fan PD et al (2015) Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 5(8):842–849. https://doi.org/10.1158/2159-8290.cd-14-1467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tong JH, Yeung SF, Chan AW et al (2016) MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis. Clin Cancer Res 22(12):3048–3056. https://doi.org/10.1158/1078-0432.CCR-3015-2061Epub 2016 Feb 3044

    Article  CAS  PubMed  Google Scholar 

  22. Frampton GM, Ali SM, Rosenzweig M et al (2015) Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov 5(8):850–859. https://doi.org/10.1158/2159-8290.cd-15-0285

    Article  CAS  PubMed  Google Scholar 

  23. Zongli Z, Matthew L, Boryana Z et al (2014) Anchored multiplex PCR for targeted next-generation sequencing. Nat Med 20(12):1479–1484

    Article  Google Scholar 

  24. Awad MM, Oxnard GR, Jackman DM et al (2016) MET exon 14 mutations in non–small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J Clin Oncol 34(7):721–730. https://doi.org/10.1200/jco.2015.63.4600

    Article  CAS  PubMed  Google Scholar 

  25. Spigel DR, Edelman MJ, O'Byrne K et al (2017) Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J Clin Oncol 35(4):412–420. https://doi.org/10.1200/jco.2016.69.2160

    Article  CAS  PubMed  Google Scholar 

  26. Neal JW, Dahlberg SE, Wakelee HA et al (2016) Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol 17(12):1661–1671. https://doi.org/10.1016/s1470-2045(16)30561-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yan SB, Um SL, Peek VL et al (2018) MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping. Invest New Drugs 36(4):536–544

    Article  CAS  PubMed  Google Scholar 

  28. Mok T, Tan E, Park K et al (2011) Randomized phase II study of ficlatuzumab (formerly AV-299), an anti-hepatocyte growth factor (HGF) monoclonal antibody (MAb) in combination with gefitinib (G) in Asian patients (pts) with NSCLC. J Clin Oncol 29 (15_suppl):TPS213

  29. Zhu M, Tang R, Doshi S et al (2015) Exposure-response analysis of rilotumumab in gastric cancer: the role of tumour MET expression. Br J Cancer 112(3):429–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bladt F, Friese-Hamim M, Ihling C et al (2014) The c-Met inhibitor MSC2156119J effectively inhibits tumor growth in liver cancer models. Cancers 6(3):1736–1752

    Article  PubMed  PubMed Central  Google Scholar 

  31. Scagliotti G, Pawel JV, Novello S et al (2015) 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. J Clin Oncol 33(24):2667–2674

    Article  CAS  PubMed  Google Scholar 

  32. Spigel DR, Ervin TJ, Ramlau RA et al (2013) Randomized phase II trial of onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 31(32):4105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Koeppen H, Yu W, Zha J et al (2014) Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib±onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit. Clin Cancer Res 20(17):4488–4498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Scagliotti G, von Pawel J, Novello S et al (2015) 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. J Clin Oncol 33(24):2667–2674. https://doi.org/10.1200/jco.2014.60.7317

    Article  CAS  PubMed  Google Scholar 

  35. Yoshioka H, Azuma K, Yamamoto N et al (2015) A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study). Ann Oncol 26(10):2066–2072. https://doi.org/10.1093/annonc/mdv288

    Article  CAS  PubMed  Google Scholar 

  36. Camidge DR, Ou SHI, Shapiro G et al (2014) Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). J Clin Oncol 32(5)

  37. Camidge DR, Otterson GA, Clark JW et al (2018) Crizotinib in patients (pts) with MET-amplified non-small cell lung cancer (NSCLC): Updated safety and efficacy findings from a phase 1 trial. Am Soc Clin Oncol

  38. Drilon A, Clark J, Weiss J et al (2018) Updated antitumor activity of crizotinib in patients with MET exon 14-altered advanced non-small cell lung cancer. J Thorac Oncol 13(10)

  39. Halliday PR, Blakely CM, Bivona TG (2019) Emerging targeted therapies for the treatment of non-small cell lung cancer. Curr Oncol Rep 21(3)

  40. Wolf J, Seto T, Han JY et al (2018) LBA52Results of the GEOMETRY mono-1 phase II study for evaluation of the MET inhibitor capmatinib (INC280) in patients (pts) with METΔex14 mutated advanced non-small cell lung cancer (NSCLC). Ann Oncol 29 (suppl_8)

  41. Wolf J, Seto T, Han J-Y et al (2019) Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. J Clin Oncol 37 (15_suppl):9004–9004. https://doi.org/10.1200/JCO.2019.37.15_suppl.9004

  42. Felip E, Horn L, Patel JD et al (2018) Tepotinib in patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon 14-skipping mutations: phase II trial. Am Soc Clin Oncol

  43. Sakai H, Veillon R, Cortot AB et al (2019) MO2-15-5 tepotinib in NSCLC patients with MET ex14 mutations: interim results from the phase II VISION study. Ann Oncol 30 (Supplement_6):mdz338. 079

  44. Tartarone A, Lerose R (2015) Clinical approaches to treat patients with non-small cell lung cancer and epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance. Therap Adv Respir Dis 9(5):242–250

    Article  CAS  Google Scholar 

  45. Juchum M, Guenther M, Laufer SA (2015) Fighting cancer drug resistance: opportunities and challenges for mutation-specific EGFR inhibitors. Drug Resist Updates 20:12–28

    Article  Google Scholar 

  46. Remon J, Morán T, Majem M et al (2014) Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: a new era begins. Cancer Treat Rev 40(1):93–101. https://doi.org/10.1016/j.ctrv.2013.06.002

    Article  CAS  PubMed  Google Scholar 

  47. Wu YL, Zhang L, Kim DW et al (2018) Phase Ib/II study of capmatinib (INC280) plus gefitinib after failure of epidermal growth factor receptor (EGFR) inhibitor therapy in patients with EGFR-mutated, MET factor-dysregulated non-small-cell lung cancer. J Clin Oncol 36(31):3101–3109. https://doi.org/10.1200/jco.2018.77.7326

    Article  CAS  PubMed  Google Scholar 

  48. Reckamp KL, Frankel PH, Ruel N et al (2019) Phase II trial of cabozantinib plus erlotinib in patients with advanced EGFR-mutant non-small cell lung cancer with progressive disease on epidermal growth factor receptor tyrosine kinase inhibitor therapy: a California Cancer Consortium Phase II Trial (NCI 9303). Front Oncol 9:132

    Article  PubMed  PubMed Central  Google Scholar 

  49. Wu Y, Cheng Y, Zhou J et al (2019) MA09. 09 Long-term outcomes to tepotinib plus gefitinib in patients with EGFR-mutant NSCLC and MET dysregulation: 18-month follow-up. J Thorac Oncol 14 (10):S284

  50. Remon J, Steuer C, Ramalingam S et al (2018) Osimertinib and other third-generation EGFR TKI in EGFR-mutant NSCLC patients. Ann Oncol 29 (suppl_1):i20–i27

  51. Mok TS, Wu Y-L, Ahn M-J et al (2017) Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 376(7):629–640

    Article  CAS  PubMed  Google Scholar 

  52. Yu H, Ahn M-J, Kim S-W et al (2019) Abstract CT032: TATTON phase Ib expansion cohort: osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-amplified NSCLC after progression on prior first/second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). AACR

  53. Sequist LV, Lee JS, Han J-Y et al (2019) Abstract CT033: TATTON phase Ib expansion cohort: osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-amplified NSCLC after progression on prior third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). AACR

  54. Haura EB, Cho BC, Lee JS et al (2019) JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC). Am Soc Clin Oncol

  55. Scagliotti G, Moro-Sibilot D, Kollmeier J et al (2019) A randomized-controlled phase 2 study of the MET antibody emibetuzumab in combination with erlotinib as first-line treatment for EGFR-mutation positive NSCLC patients. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2019.10.003

    Article  PubMed  Google Scholar 

  56. Sabari JK, Leonardi GC, Shu CA et al (2018) PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers. Ann Oncol 29(10):2085–2091. https://doi.org/10.1093/annonc/mdy334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mazieres J, Drilon AE, Mhanna L et al (2018) Efficacy of immune-checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) patients harboring activating molecular alterations (ImmunoTarget). Am Soc Clin Oncol

  58. Sabari JK, Montecalvo J, Chen R et al (2017) PD-L1 expression and response to immunotherapy in patients with MET exon 14-altered non-small cell lung cancers (NSCLC). Am Soc Clin Oncol

  59. Recondo Jr G, Bahcall M, Sholl L et al (2019) MA09.11 mechanisms of resistance to MET tyrosine kinase inhibitors in patients with MET exon 14 mutant non-small cell lung cancer. J Thorac Oncol 14(10):S285. https://doi.org/10.1016/j.jtho.2019.08.573

  60. Engstrom LD, Aranda R, Lee M et al (2017) Glesatinib exhibits antitumor activity in lung cancer models and patients harboring MET exon 14 mutations and overcomes mutation-mediated resistance to type I MET inhibitors in nonclinical models. Clin Cancer Res 23(21):6661–6672. https://doi.org/10.1158/1078-0432.ccr-17-1192

    Article  CAS  PubMed  Google Scholar 

  61. Fujino T, Kobayashi Y, Suda K et al (2019) Sensitivity and resistance of MET exon 14 mutations in lung cancer to eight MET tyrosine kinase inhibitors in vitro. J Thorac Oncol 14(10):1753–1765. https://doi.org/10.1016/j.jtho.2019.06.023

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China

    Xiaoqing Yu & Yun Fan

  2. Department of Medical Oncology, Cancer Hospital, University of Chinese Academy of Sciences, Hangzhou, China

    Xiaoqing Yu, Sizhe Yu & Yun Fan

  3. Department of Medical Oncology, Zhejiang Cancer Hospital, No 1 Banshandong Road, Gongshu District, Hangzhou, Zhejiang, China

    Xiaoqing Yu, Sizhe Yu & Yun Fan

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Yu, X., Yu, S. & Fan, Y. Progress on treatment of MET signaling pathway in non-small cell lung cancer. Int J Clin Oncol 25, 1450–1458 (2020). https://doi.org/10.1007/s10147-020-01702-0

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