MET 14外显子跳跃突变在非小细胞肺癌中的研究进展

^{610041 成都，四川大学华西医院胸部肿瘤科, Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu 610041, China,}

卢铀 (You LU): moc.liamtoh@uluoydar

卢铀, You LU, E-mail: moc.liamtoh@uluoydar

卢铀 (You LU): moc.liamtoh@uluoydar

Received 2017 Dec 29; Revised 2018 Mar 3; Accepted 2018 Mar 29.

Abstract

近年来，靶向治疗在非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的治疗中取得了巨大成功。间质-上皮细胞转化因子（mesenchymal-epithelial transition factor, MET）被认为是继表皮生长因子受体（epidermal growth factor receptor, EGFR）、间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）之后又一重要的NSCLC分子治疗靶点。MET 14外显子跳跃突变患者在一些临床试验及个案报道中显示出对MET抑制剂良好的疗效，提示MET 14外显子跳跃突变或可成为靶向治疗的良好指标，但这仍需大样本量的临床研究来证实。本文就MET 14外显子跳跃突变的分子机制、人群特征、治疗策略及耐药机制作一综述。

Keywords: 肺肿瘤, MET, 酪氨酸激酶抑制剂, 克唑替尼, 靶向治疗

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: Lung neoplasms, MET, Tyrosine kinase inhibitors, Crizotinib, Targeted therapy

Abstract

尽管目前肺癌仍然是世界上致死率最高的肿瘤，但在具有某些特定基因突变的非小细胞肺癌（non-small cell lung cancer, NSCLC）患者中，靶向治疗的出现使患者的预后有了较大的提升¹, 2]。间质-上皮细胞转化因子（mesenchymal-epithelial transition factor, MET）与表皮生长因子受体（epidermal growth factor receptor, EGFR），鼠类肉瘤病毒癌基因（kirsten rat sarcoma viral oncogene, KRAS）等癌基因近乎同时被发现（1984年）³]。然而与同时代分子靶点的瞩目成果不同的是，尽管目前已经研制出超过20种靶向MET及其配体肝细胞生长因子（hepatocyte growth factor, HGF）的药物，数个Ⅲ期临床试验均以失败告终⁴, 5]。近年来，越来越多的证据表明MET抑制剂在MET 14外显子跳跃突变的患者中取得了良好的抗肿瘤效果，提示MET 14外显子跳跃突变或可作为NSCLC患者治疗的新靶点⁶]。本文就MET 14外显子跳跃突变的分子机制、人群特征、治疗策略及耐药机制进行综述。

致谢

感谢辉瑞医学部刘芳博士给予的文献查阅的支持。

致谢

Funding Statement

本文受国家自然科学基金（No.81472196）和四川省基础研究计划基金（No.2016JY0050）资助

This paper was supported by the grants from the National Natural Science Foundation of China (No.81472196) and Sichuan Province Research Foundation for Basic Research (No.2016JY0050)(Both to You LU)

Funding Statement

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.] [[Google Scholar]
2. 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.] [[PubMed][Google Scholar]
3. 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.] [[PubMed][Google Scholar]
4. 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.] [[PubMed][Google Scholar]
5. 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.] [[PubMed][Google Scholar]
6. Salgia RMET 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.] [[PubMed][Google Scholar]
7. Awad MMImpaired 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.] [[PubMed][Google Scholar]
8. 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.] [[Google Scholar]
9. Cancer Genome Atlas Research NComprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543–550. doi: 10.1038/nature13385.] [[Google Scholar]
10. 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.] [[PubMed][Google Scholar]
11. 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.] [[PubMed][Google Scholar]
12. 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.] [[PubMed][Google Scholar]
13. 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.] [[PubMed][Google Scholar]
14. 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.] [[PubMed][Google Scholar]
15. 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: 10.1158/2159-8290.CD-15-0285.] [[PubMed][Google Scholar]
16. 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.] [[Google Scholar]
17. 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.] [[PubMed][Google Scholar]
18. 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.] [[PubMed][Google Scholar]
19. 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.] [[PubMed][Google Scholar]
20. 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.] [[PubMed][Google Scholar]
21. 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.] [[PubMed][Google Scholar]
22. 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.] [[Google Scholar]
23. 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.] [[Google Scholar]
24. 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.] [
25. 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.] [[PubMed]
26. 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: 10.1158/2159-8290.cd-14-1467.] [[Google Scholar]
27. 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.] [[PubMed][Google Scholar]
28. Garber KMET inhibitors start on road to recovery. Nat Rev Drug Discov. 2014;13(8):563–565. doi: 10.1038/nrd4406.] [[PubMed][Google Scholar]
29. Yap TA, Popat STargeting 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.] [[PubMed][Google Scholar]
30. Drilon AMET 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.] [[Google Scholar]
31. 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.] [[PubMed][Google Scholar]
32. 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.] [[PubMed][Google Scholar]
33. 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.] [[PubMed][Google Scholar]
34. 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.] [[PubMed][Google Scholar]
35. 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.] [[PubMed][Google Scholar]
36. 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: 10.1158/2159-8290.cd-16-0686.] [[Google Scholar]
37. 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.] [[PubMed][Google Scholar]