Crepaldi Tiziana, Gallo Simona, Comoglio Paolo Maria
Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy.
Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy.
Pharmaceuticals (Basel). 2024 Mar 30;17(4):448. doi: 10.3390/ph17040448.
The discovery and subsequent research on the MET oncogene's role in cancer onset and progression have illuminated crucial insights into the molecular mechanisms driving malignancy. The identification of MET as the hepatocyte growth factor (HGF) receptor has paved the path for characterizing the MET tyrosine kinase activation mechanism and its downstream signaling cascade. Over the past thirty years, research has established the importance of HGF/MET signaling in normal cellular processes, such as cell dissociation, migration, proliferation, and cell survival. Notably, genetic alterations that lead to the continuous activation of MET, known as constitutive activation, have been identified as oncogenic drivers in various cancers. The genetic lesions affecting MET, such as exon skipping, gene amplification, and gene rearrangements, provide valuable targets for therapeutic intervention. Moreover, the implications of MET as a resistance mechanism to targeted therapies emphasize the need for combination treatments that include MET inhibitors. The intriguing "flare effect" phenomenon, wherein MET inhibition can lead to post-treatment increases in cancer cell proliferation, underscores the dynamic nature of cancer therapeutics. In human tumors, increased protein expression often occurs without gene amplification. Various mechanisms may cause an overexpression: transcriptional upregulation induced by other oncogenes; environmental factors (such as hypoxia or radiation); or substances produced by the reactive stroma, such as inflammatory cytokines, pro-angiogenic factors, and even HGF itself. In conclusion, the journey to understanding MET's involvement in cancer onset and progression over the past three decades has not only deepened our knowledge, but has also paved the way for innovative therapeutic strategies. Selective pharmacological inactivation of MET stands as a promising avenue for achieving cancer remission, particularly in cases where MET alterations are the primary drivers of malignancy.
MET原癌基因在癌症发生和发展中的作用的发现及后续研究，为深入了解驱动恶性肿瘤的分子机制提供了关键见解。MET作为肝细胞生长因子（HGF）受体的鉴定，为表征MET酪氨酸激酶激活机制及其下游信号级联铺平了道路。在过去三十年中，研究已证实HGF/MET信号在正常细胞过程（如细胞解离、迁移、增殖和细胞存活）中的重要性。值得注意的是，导致MET持续激活的基因改变，即组成性激活，已被确定为各种癌症中的致癌驱动因素。影响MET的基因损伤，如外显子跳跃、基因扩增和基因重排，为治疗干预提供了有价值的靶点。此外，MET作为靶向治疗耐药机制的影响强调了联合使用MET抑制剂进行治疗的必要性。有趣的“flare效应”现象，即MET抑制可导致治疗后癌细胞增殖增加，突显了癌症治疗的动态性质。在人类肿瘤中，蛋白质表达增加往往在没有基因扩增的情况下发生。多种机制可能导致过表达：由其他癌基因诱导的转录上调；环境因素（如缺氧或辐射）；或反应性基质产生的物质，如炎性细胞因子、促血管生成因子，甚至HGF本身。总之，在过去三十年中，了解MET在癌症发生和发展中的作用的历程不仅加深了我们的认识，也为创新治疗策略铺平了道路。MET的选择性药理学失活是实现癌症缓解的一个有前景的途径，特别是在MET改变是恶性肿瘤主要驱动因素的情况下。
