The Hepatocyte Growth Factor Receptor: Structure, Function and Pharmacological Targeting in Cancer

Fabiola      Cecchi; Daniel      C. Rabe; Donald      P. Bottaro

doi:10.2174/157436211795659955

Abstract

Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. Pathway inhibitors can be divided broadly into biologicals and low molecular weight synthetic TK inhibitors; of these, the latter now outnumber all other inhibitor types. We review here Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment include optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control.

Keywords: Hepatocyte growth factor, Met, Grb2/SOS, Gab1, PI3 kinase, Stat3, Wnt signaling, Rho/Rac, Protein Kinase C, protein tyrosine phosphates, MAPK, mTOR, ERK, Mcl-1, RAS, MEK, LKB1, Cdc42, Mig6, Phospholipase C g-, cRaf, Catenin, Paxillin, FAK