HGF-Met通路是细胞信号传导的重要通路之一，其在胚胎、器官形态发育以及血管发生等生理过程中发挥着重要作用。细胞过度表达HGF或Met时，常常促进肿瘤细胞的生长、侵袭和转移。与此同时，HGF表达增加会过度激活Met介导的PI3K-Akt信号通路，降低EGFR-TKI对这种信号级联反应的抑制。原癌基因Met编码的c-Met是一种具有高度结合性的受体酪氨酸激酶，属于RON亚族，是散射因子或肝细胞生长因子（HGF）唯一已知的受体，HGF与c-Met胞外域结合后，诱导c-Met发生磷酸化，C端多功能区域会募集如GAB1、GAB2等因子，进一步结合PI3K等蛋白分子，由此激活RASMAPK、PI3K-ATK等信号通路，从而影响细胞生长、增殖。c-Met通路异常会引起肿瘤的发生和转移。c-Met抑制剂PF-02341066、ARQ-197与AZD-9291联合用药可明显抑制耐药瘤株的增殖活性。

参考文献：

[1] 许贤, 陈立学, 许佑君. 治疗非小细胞肺癌EGFR抑制剂及其联合用药的研究进展[J]. 中南药学, 2018, 16(11): 1584-1594.

[2] 耿传荣，邓玉晓，崔新强, 等. 表皮生长因子受体抑制剂用于肺癌治疗的最新研究进展[J]. 中国药学杂志, 2018, 53(13): 1037-1046.

[3] Zhou WJ, Ercan D, Chen L, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M [J]. Nature, 2009, 462(24): 1070-1074.

[4] Walter AO, Sjin RTT, Haringsma HJ, et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790Mmediated resistance in NSCLC [J]. Cancer Discov, 2013, 3(12): 1404-1415.

[5] Finlay MR, Anderton M, Ashton S, et al. Discovery of Potent and Selective EGFR Inhibitor(AZD9291)of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor [J]. J Med Chem, 2014, 57(20): 8249-8267.

[6] Ward RA, Anderton MJ, Ashton S, et al. Structure and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor(EGFR) [J]. J Med Chem, 2013, 56(17): 7025-7048.

[7] Park K, Lee JS, Han JY, et al. 1300: efficacy and safety of BI 1482694(HM61713), an EGFR mutant-specific inhibitor, in T790M-positive NSCLC at the recommended phase Ⅱ dose [J]. J Thorac Oncol, 2016, 11(4): S113-S113.

[8] GUNTHEＲ M, JUCHUM M, KELTEＲ G, et al. Lung cancer: EGFR inhibitors with low nanomolar activity against a therapy-resistant L858R/T790M/C797S mutant  [J]. Angewand Chem, 2016, 55(36): 10890-10894．

[9] JIA Y, YUN C H, PAＲK E, et al. Overcoming EGFＲ(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors [J]. Nature, 2016, 534(7605) : 129-132．

[10] Pirker, R., & Filipits, M. Monoclonal antibodies against EGFR in non-small cell lung cancer [J]. Critical Reviews in Oncology/Hematology, 2011, 80(1): 1–9.