Clinical Development of MET Targeted Therapy For Human Cancer

Nima      Tirgan; Zhe      Tang; Patrick   C.   Ma

doi:10.2174/157339409789712708

Abstract

MET is a member of the semaphorins, plexins and MET/RON receptor family, which is stimulated by the ligand hepatocyte growth factor (HGF) and uniquely regulates a wide range of cellular functions. When dysregulated and activated, as in the case of human cancers with MET amplification or overexpression, mutation or alternative splicing, it has been implicated to play pivotal role in human tumor cell progression and metastasis. MET-HGF signal path has been shown to be attractive therapeutic target for human cancer novel therapy. In recent years, substantial progresses have been achieved to advance MET-HGF inhibitory strategies from the bench-top preclinical studies to clinical trial studies. Targeting agents being developed include not only various small molecule MET inhibitors, but also specific anti-MET or anti- HGF antibodies. Current emerging knowledge of the kinases signaling cross-talk networks will eventually facilitate rational design of optimal treatment strategies combining MET inhibition with other inhibitors, such as erlotinib (against EGFR). In this review, we summarize the relevant MET receptor biology, mutations (especially non-kinase domain mutations) and other genomic alterations in human cancers. The strategies to inhibit MET-HGF as novel therapy in human cancer as well as agents undergoing clinical trial studies would be discussed. Finally, we also summarize the various challenges to be met, including predictive biomarkers identification, patient selection, and rational combinational treatment approaches.

Keywords: MET, inhibition, cancer, molecular target, novel therapy

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