[MET Exon 14 Skipping Mutations in Non-small Cell Lung Cancer]

Limei Yin, You Lu, Limei Yin, You Lu

Abstract

Recently, targeted therapy has achieved great success in the treatment of non-small cell lung cancer (NSCLC) patients. Mesenchymal to epithelial transition factor (MET) is considered to be another important molecular target for NSCLC since epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Accumulating clinical trials and case reports have confirmed that MET inhibitors exhibited a potential prospect in treating patients with MET 14 exon skipping alterations, suggesting that MET 14 exon skipping mutation might be an effective biomarker for MET inhibitors, which remains to be confirmed by more clinical data. This review summarizes current research about the molecular mechanism, clinicopathological characterization, treatment strategies and drug resistance mechanisms of MET 14 exon skipping alterations in NSCLC. .

Keywords: Crizotinib; Lung neoplasms; MET; Targeted therapy; Tyrosine kinase inhibitors.

Figures

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MET 14外显子跳跃突变的分子机制。 The molecular mechanism of MET exon 14 skipping.

References

    1. Sabari JK, Santini F, Bergagnini I, et al. Changing the therapeutic landscape in non-small cell lung cancers: the evolution of comprehensive molecular profiling improves access to therapy. Curr Oncol Rep. 2017;19(4):24. doi: 10.1007/s11912-017-0587-4.
    1. Park SJ, More S, Murtuza A, et al. New targets in non-small cell lung cancer. Hematol Oncol Clin North Am. 2017;31(1):113–129. doi: 10.1016/j.hoc.2016.08.010.
    1. Cooper CS, Park M, Blair DG, et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature. 1984;311(5981):29–33. doi: 10.1038/311029a0.
    1. Scagliotti G, von Pawel J, Novello S, 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. J Clin Oncol. 2015;33(24):2667–2674. doi: 10.1200/jco.2014.60.7317.
    1. Spigel DR, Edelman MJ, O'Byrne K, et al. 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. 2017;35(4):412–420. doi: 10.1200/jco.2016.69.2160.
    1. Salgia R. MET in lung cancer: Biomarker selection based on scientific rationale. Mol Cancer Ther. 2017;16(4):555–565. doi: 10.1158/1535-7163.mct-16-0472.
    1. Awad MM. Impaired c-MET receptor degradation mediated by MET exon 14 mutations in non-small-cell lung cancer. J Clin Oncol. 2016;34(8):879–881. doi: 10.1200/jco.2015.64.2777.
    1. Drilon A, Cappuzzo F, Ou SI, et al. Targeting MET in lung cancer: will expectations finally be MET? J Thorac Oncol. 2017;12(1):15–26. doi: 10.1016/j.jtho.2016.10.014.
    1. Cancer Genome Atlas Research N. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543–550. doi: 10.1038/nature13385.
    1. Awad MM, Oxnard GR, Jackman DM, et al. 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. 2016;34(7):721–730. doi: 10.1200/JCO.2015.63.4600.
    1. Gow CH, Hsieh MS, Wu SG, et al. A comprehensive analysis of clinical outcomes in lung cancer patients harboring a MET exon 14 skipping mutation compared to other driver mutations in an East Asian population. Lung Cancer. 2017;103:82–89. doi: 10.1016/j.lungcan.2016.12.001.
    1. Tong JH, Yeung SF, Chan AW, et al. MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis. Clin Cancer Res. 2016;22(12):3048–3056. doi: 10.1158/1078-0432.ccr-15-2061.
    1. Lee GD, Lee SE, Oh DY, et al. MET exon 14 skipping mutations in lung adenocarcinoma: clinicopathologic implications and prognostic values. J Thorac Oncol. 2017;12(8):1233–1246. doi: 10.1016/j.jtho.2017.04.031.
    1. Cortot AB, Kherrouche Z, Descarpentries C, et al. Exon 14 deleted MET receptor as a new biomarker and target in cancers. J Natl Cancer Inst. 2017;109(5) doi: 10.1093/jnci/djw262.
    1. Frampton GM, Ali SM, Rosenzweig M, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 2015;5(8):850–859. doi: 10.1158/-15-0285.
    1. Heist RS, Shim HS, Gingipally S, et al. MET exon 14 skipping in non-small cell lung cancer. Oncologist. 2016;21(4):481–486. doi: 10.1634/theoncologist.2015-0510.
    1. Liu X, Jia Y, Stoopler MB, et al. Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations. J Clin Oncol. 2016;34(8):794–802. doi: 10.1200/JCO.2015.62.0674.
    1. Liu SY, Gou LY, Li AN, et al. The unique characteristics of MET exon 14 mutation in chinese patients with NSCLC. J Thorac Oncol. 2016;11(9):1503–1510. doi: 10.1016/j.jtho.2016.05.016.
    1. Kwon D, Koh J, Kim S, et al. MET exon 14 skipping mutation in triple-negative pulmonary adenocarcinomas and pleomorphic carcinomas: An analysis of intratumoral MET status heterogeneity and clinicopathological characteristics. Lung Cancer. 2017;106:131–137. doi: 10.1016/j.lungcan.2017.02.008.
    1. Schrock AB, Frampton GM, Suh J, et al. Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations. J Thorac Oncol. 2016;11(9):1493–1502. doi: 10.1016/j.jtho.2016.06.004.
    1. Lee C, Usenko D, Frampton GM, et al. MET 14 deletion in sarcomatoid non-small-cell lung cancer detected by next-generation sequencing and successfully treated with a MET inhibitor. J Thorac Oncol. 2015;10(12):e113–e114. doi: 10.1097/jto.0000000000000645.
    1. Jorge SE, Schulman S, Freed JA, et al. Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation. Lung Cancer. 2015;90(3):369–374. doi: 10.1016/j.lungcan.2015.10.028.
    1. Jenkins RW, Oxnard GR, Elkin S, et al. Response to crizotinib in a patient with lung adenocarcinoma harboring a MET splice site mutation. Clin Lung Cancer. 2015;16(5):e101–e104. doi: 10.1016/j.cllc.2015.01.009.
    1. Waqar SN, Morgensztern D, Sehn J. MET mutation associated with responsiveness to crizotinib. J Thorac Oncol. 2015;10(5):e29–e31. doi: 10.1097/jto.0000000000000478.
    1. Mendenhall MA, Goldman JW. MET-mutated NSCLC with major response to crizotinib. J Thorac Oncol. 2015;10(5):e33–e34. doi: 10.1097/jto.0000000000000491.
    1. Paik PK, Drilon A, Fan PD, et al. Response to MET inhibitors in patients with stage Ⅳ lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 2015;5(8):842–849. doi: 10.1158/-14-1467.
    1. Mahjoubi L, Gazzah A, Besse B, et al. A never-smoker lung adenocarcinoma patient with a MET exon 14 mutation (d1028n) and a rapid partial response after crizotinib. Invest New Drugs. 2016;34(3):397–398. doi: 10.1007/s10637-016-0332-0.
    1. Garber K. MET inhibitors start on road to recovery. Nat Rev Drug Discov. 2014;13(8):563–565. doi: 10.1038/nrd4406.
    1. Yap TA, Popat S. Targeting MET exon 14 skipping alterations: has lung cancer MET its match? J Thorac Oncol. 2017;12(1):12–14. doi: 10.1016/j.jtho.2016.10.019.
    1. Drilon A. MET exon 14 alterations in lung cancer: exon skipping extends half-life. Clin Cancer Res. 2016;22(12):2832–2834. doi: 10.1158/1078-0432.ccr-16-0229.
    1. Ou S-HI, Young L, Schrock AB, et al. Emergence of preexisting MET y1230c mutation as a resistance mechanism to crizotinib in NSCLC with MET exon 14 skipping. J Thorac Oncol. 2017;12(1):137–140. doi: 10.1016/j.jtho.2016.09.119.
    1. Heist RS, Sequist LV, Borger D, et al. Acquired resistance to crizotinib in NSCLC with MET exon 14 skipping. J Thorac Oncol. 2016;11(8):1242–1245. doi: 10.1016/j.jtho.2016.06.013.
    1. Reungwetwattana T, Liang Y, Zhu V, et al. 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. 2017;103:27–37. doi: 10.1016/j.lungcan.2016.11.011.
    1. Engstrom LD, Aranda R, Lee M, et al. 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. 2017;23(21):6661–6672. doi: 10.1158/1078-0432.ccr-17-1192.
    1. Tiedt R, Degenkolbe E, Furet P, et al. A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients. Cancer Res. 2011;71(15):5255–5264. doi: 10.1158/0008-5472.can-10-4433.
    1. Bahcall M, Sim T, Paweletz CP, et al. Acquired METD1228V mutation and resistance to MET inhibition in lung cancer. Cancer Discov. 2016;6(12):1334–1341. doi: 10.1158/-16-0686.
    1. Klempner SJ, Borghei A, Hakimian B, et al. Intracranial activity of cabozantinib in MET exon 14-positive NSCLC with brain metastases. J Thorac Oncol. 2017;12(1):152–156. doi: 10.1016/j.jtho.2016.09.127.

Source: PubMed

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