Met Signaling in Carcinogenesis

The hepatocyte growth factor (HGF)/Met receptor tyrosine kinase signaling pathway is an essential regulator of cell proliferation, motility, and morphogenesis during embryogenesis, early development, and adult homeostasis. Signaling is directly regulated at several levels, including HGF proteolytic activation, receptor and proteoglycan binding, receptor phosphorylation, and ligand-receptor complex internalization and degradation. In many types of cancer, events that undermine these features can lead to aberrant pathway activation and contribute to oncogenesis, tumor angiogenesis and invasiveness, and tumor metastasis. Advanced drug design strategies and lessons learned from other growth factor/tyrosine kinase-targeted drug programs fueled the rapid development of potent and highly selective HGF/Met-targeted drug candidates. Meaningful clinical responses from early-phase clinical trials have been reported in lung, gastric, prostate, and papillary renal cancer patients treated with HGF and Met inhibitors. Yet, most of these agents have not advanced beyond phase II testing, a few stopped in phase III trials, and many HGF/Met-targeted drug development programs have been halted. No selective Met pathway inhibitors have been FDA approved for a disease where Met is thought to be a primary contributor. Underlying this unanticipated failure are a multitude of factors, but inadequate development of clinical tests for HGF/Met pathway activity and criticality appears to have been a critical weakness. This realization, our growing awareness of the molecular diversity of oncogenic defects in solid tumors, the need to modernize clinical trial design for testing highly targeted drugs as single agents, and the need to better translate combination therapies from model systems to human patients, should prevent us from discarding drugs that may have unrealized clinical utility, and help us identify indications and patients where they are most efficacious.