C-Met and hepatocyte growth factor: Potential as novel targets in cancer therapy

Abstract

Receptor tyrosine kinases have come to fruition as therapeutic targets in a variety of malignancies. In this group of targets, the c-Met receptor tyrosine kinase plays an important role in increased cell growth, reduced apoptosis, altered cytoskeletal function, increased metastasis, and other biologic changes. The ligand for c-Met is hepatocyte growth factor (HGF), also known as scatter factor. Met is overexpressed and mutated in a variety of malignancies, among which germline mutations are of particular interest. Most mutations of Met have been found in the juxtamembrane, the tyrosine kinase, and the semaphorin domain. Met gain-of-function mutations lead to deregulated or prolonged tyrosine kinase activity, which is instrumental to its transforming activity. This review summarizes the biologic functions regulated by Met and its structural requirements as well as related developments in targeted therapy. Treatment approaches, including antagonism of HGF binding to Met, targeting of RNA and the Met protein, and inhibition of the tyrosine kinase domain of Met, are highlighted. Targeting of the HGF/Met pathway, alone or in combination with standard therapies, is likely to improve current therapies in Met-dependent malignancies.