文章：

已知的和新的MET癌基因在癌症中的作用：一种连贯的靶向治疗方法

Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy

原文发布日期：2018-04-19

DOI: 10.1038/s41568-018-0002-y

类型: Review Article

开放获取: 否

英文摘要：

The MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it initiates and sustains neoplastic transformation when genetically altered (‘oncogene addiction’) and fosters cancer cell survival and tumour dissemination when transcriptionally activated in the context of an adaptive response to adverse microenvironmental conditions (‘oncogene expedience’). Moreover, MET is an intrinsic modulator of the self-renewal and clonogenic ability of cancer stem cells (‘oncogene inherence’). Here, we provide the latest findings on MET function in cancer by focusing on newly identified genetic abnormalities in tumour cells and recently described non-mutational MET activities in stromal cells and cancer stem cells. We discuss how MET drives cancer clonal evolution and progression towards metastasis, both ab initio and under therapeutic pressure. We then elaborate on the use of MET inhibitors in the clinic with a critical appraisal of failures and successes. Ultimately, we advocate a rationale to improve the outcome of anti-MET therapies on the basis of thorough consideration of the entire spectrum of MET-mediated biological responses, which implicates adequate patient stratification, meaningful biomarkers and appropriate clinical end points.

摘要翻译： 

MET癌基因编码一种具有多效性功能的非常规受体酪氨酸激酶：当基因发生改变时（“癌基因成瘾”），它启动并维持肿瘤转化；当在适应不利微环境条件的转录激活背景下（“癌基因权宜”），它促进癌细胞存活和肿瘤扩散。此外，MET是癌症干细胞自我更新和克隆形成能力的内在调节因子（“癌基因固有”）。本文通过重点关注新发现的肿瘤细胞遗传异常以及近期描述的基质细胞和癌症干细胞中的非突变MET活性，提供了关于MET在癌症中功能的最新发现。我们讨论了MET如何驱动癌症克隆进化及向转移灶的进展，包括从起始阶段到治疗压力下的过程。随后我们详细阐述了MET抑制剂在临床中的应用，并对失败与成功案例进行了批判性评估。最后，我们提出基于全面考量MET介导的生物学反应全谱的策略——这涉及合理的患者分层、有意义的生物标志物和恰当的临床终点——以改善抗MET治疗结局的理论依据。

原文链接：

Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy