title: c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention.
abstract: Receptor tyrosine kinase (RTK) targeted agents such as trastuzumab, imatinib, bevacizumab, and gefitinib inhibitors have illustrated the utility of targeting this protein class for treatment of selected cancers. A unique member of the RTK family, c-Met, also represents an intriguing target for cancer therapy that is yet to be explored in a clinical setting. The proto-oncogene, c-Met, encodes the high-affinity receptor for hepatocyte growth factor (HGF) or scatter factor (SF). c-Met and HGF are each required for normal mammalian development and have been shown to be particularly important in cell migration, morphogenic differentiation, and organization of three-dimensional tubular structures (e.g. renal tubular cells, gland formation, etc.) as well as cell growth and angiogenesis. Both c-Met and HGF have been shown to be deregulated in and to correlate with poor prognosis in a number of major human cancers. New data describing the constitutive phosphorylation of c-Met in a number of human tumors is presented here along with a variety of mechanisms by which c-Met can become activated, including mutation and gene amplification. In support of the clinical data implicating c-Met activation in the pathogenesis of human cancers, introduction of c-Met and HGF (or mutant c-Met) into cells conferred the properties of motility, invasiveness, and tumorgenicity to the transformed cells. Conversely, the inhibition of c-Met with a variety of receptor antagonists inhibited the motility, invasiveness, and tumorgenicity of human tumor cell lines. Consistent with this observation, small-molecule inhibitors of c-Met were developed that antagonized c-Met/HGF-dependent phenotypes and tumor growth in mouse models. This review will address the potential for development of c-Met inhibitors for treatment of human cancers with particular emphasis on recent findings with small-molecule inhibitors.
authors.affiliation: Research Pharmacology, Pfizer Inc., La Jolla, CA 92121, USA. james.christensen@pfizer.com
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Jon
authors.initials: J
authors.lastname: Burrows
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005784:Gene Amplification; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D009389:Neovascularization, Pathologic; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met