Targeting MET in cancer: rationale and progress

Key Points 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. 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. 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. 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. 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. 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 in