文章：

靶向MET治疗癌症：理论基础和进展

Targeting MET in cancer: rationale and progress

原文发布日期：2012-01-24

DOI: 10.1038/nrc3205

类型: Review Article

开放获取: 否

要点：

1. The growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor tyrosine kinase MET, the product of the MET proto-oncogene, provide essential signals for survival and long-distance migration of epithelial and myogenic precursor cells during embryogenesis. Cancer cells hijack HGF/SF–MET for invasion and metastasis, hence these molecules have emerged as key targets for cancer therapy.
2. Aberrant MET activation occurs in many types of cancer, and results from multiple mechanisms. Many carcinomas overexpress MET and the surrounding stroma overexpresses HGF/SF. Furthermore, certain patients with renal papillary, hepatocellular or gastric carcinomas carry point mutations in MET. These mutations have proved important in demonstrating a causal role of aberrant MET signalling in human cancer.
3. The intracellular signalling cascades activated by MET include the PI3K–AKT, RAC1–cell division control protein 42 (CDC42), RAP1 and RAS–MAPK pathways. An intricate network of cross-signalling involving the MET–epidermal growth factor receptor (EGFR), MET–vascular endothelial growth factor receptor (VEGFR) and MET–WNT pathways has also emerged in the past few years. This signalling network has major implications for therapy.
4. Structural studies of HGF/SF, the MET ectodomain and the pathways involved in activation of the precursor form of HGF/SF (pro-HGF/SF) have yielded important results and new opportunities for therapeutic intervention, namely specific inhibitors of the major HGF/SF activators, HGF/SF fragments with antagonistic activity — such as NK4 — and HGF/SF and MET antibodies.
5. Parallel efforts in the structural analysis of the MET kinase have led to extensive progress in the development of MET kinase inhibitors for cancer therapy, and three major classes of inhibitors have emerged from this work that differ in their binding mode, activity on MET kinase mutants and enzyme specificity.
6. A number of recent clinical trials have demonstrated strong activity of MET inhibitors in patients with a variety of advanced or metastatic tumours, including non-small-cell lung cancer (NSCLC), and breast, prostate, liver and renal cancer. MET inhibitors have also displayed clinical benefits in patients with NSCLC and patients with breast cancer who had developed resistance to EGFR therapy. These recent data clearly indicate that HGF/SF–MET therapeutics may have potential in several groups of cancer patients either alone or in combination with inhibitors of other signalling pathways.

要点翻译：

1. 生长和运动因子肝细胞生长因子/扩散因子（HGF/SF）及其受体酪氨酸激酶MET（MET原癌基因的产物）在胚胎发生过程中为上皮和肌源性前体细胞的存活及远距离迁移提供关键信号。癌细胞通过劫持HGF/SF–MET系统实现侵袭和转移，因此这些分子已成为癌症治疗的重要靶点。
2. 异常MET激活见于多种癌症类型，其发生机制多样。许多癌组织过度表达MET，而周围基质则过度表达HGF/SF。此外，部分肾乳头状癌、肝细胞癌或胃癌患者携带MET点突变。这些突变在证明异常MET信号传导与人类癌症因果关系方面具有重要作用。
3. MET激活的细胞内信号级联包括PI3K–AKT、RAC1–细胞分裂控制蛋白42（CDC42）、RAP1和RAS–MAPK通路。过去几年中还发现了一个由MET-表皮生长因子受体（EGFR）、MET-血管内皮生长因子受体（VEGFR）和MET-WNT通路构成的复杂交叉信号网络，该信号网络对治疗策略具有重要影响。
4. 对HGF/SF、MET胞外域及HGF/SF前体形式（pro-HGF/SF）激活通路的结构研究已取得重要成果，为治疗干预提供了新机遇：包括主要HGF/SF激活剂的特异性抑制剂、具有拮抗活性的HGF/SF片段（如NK4），以及HGF/SF和MET抗体。
5. 同期开展的MET激酶结构分析推动了癌症治疗用MET激酶抑制剂的重大进展，根据结合模式、对MET激酶突变体的活性及酶特异性差异，目前已开发出三大类抑制剂。
6. 近期多项临床试验表明，MET抑制剂在晚期或转移性肿瘤患者（包括非小细胞肺癌、乳腺癌、前列腺癌、肝癌和肾癌）中表现出强劲活性。该抑制剂还对EGFR治疗产生耐药性的非小细胞肺癌和乳腺癌患者显现临床获益。这些最新数据清晰表明，HGF/SF–MET靶向治疗单独使用或与其他信号通路抑制剂联用，在多种癌症患者群体中具有应用潜力。

英文摘要：

Uncontrolled cell survival, growth, angiogenesis and metastasis are essential hallmarks of cancer. Genetic and biochemical data have demonstrated that the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the tyrosine kinase MET, have a causal role in all of these processes, thus providing a strong rationale for targeting these molecules in cancer. Parallel progress in understanding the structure and function of HGF/SF, MET and associated signalling components has led to the successful development of blocking antibodies and a large number of small-molecule MET kinase inhibitors. In this Review, we discuss these advances, as well as results from recent clinical studies that demonstrate that inhibiting MET signalling in several types of solid human tumours has major therapeutic value.

摘要翻译： 

不受控制的细胞存活、生长、血管生成和转移是癌症的重要特征。遗传学和生化数据已证实，生长因子肝细胞生长因子/分散因子（HGF/SF）及其受体——酪氨酸激酶MET，在这些过程中均具有因果作用，从而为靶向这些分子治疗癌症提供了充分依据。与此同时，对HGF/SF、MET及其相关信号组分的结构与功能认识的同步进展，已成功促成阻断性抗体和大量小分子MET激酶抑制剂的开发。本文综述了这些进展，以及近期临床研究的结果；这些研究表明，在多种人类实体瘤中抑制MET信号通路具有显著的治疗价值。

原文链接：

Targeting MET in cancer: rationale and progress