The MET Oncogene as a Therapeutical Target in Cancer Invasive Growth

Abstract

The MET proto-oncogene, encoding the tyrosine kinase receptor for Hepatocyte Growth Factor (HGF) regulates invasive growth, a genetic program that associates control of cell proliferation with invasion of the extracellular matrix and protection from apoptosis. Physiologically, invasive growth takes place during embryonic development, and, in post-natal life, in wound healing and regeneration of several tissues. The MET oncogene is overexpressed and/or genetically mutated in many tumors, thereby sustaining pathological invasive growth, a prerequisite for metastasis. MET is the subject of intense research as a target for small molecule kinase inhibitors and, together with its ligand HGF, for inhibitory antibodies. The tight interplay of MET with the protease network has unveiled mechanisms to be exploited to achieve effective inhibition of invasive growth.

Keywords: MET oncogene; antibody; invasion; metastasis; microenvironment; proteases; small molecule kinase inhibitors; targeted therapy.

Figure 1

Schematic representation of the receptor tyrosine kinase encoded by the MET oncogene, its ligand HGF, and the main experimental drugs against the receptor or the ligand currently under investigation (engineered MET/HGF antagonists, anti-HGF antibodies, anti-Met antibodies, small-molecule Met inhibitors). The α and β chains of both receptor and ligand are represented. In the receptor, the aminoacidic residues undergoing phosphorylation during signal activation are also indicated. For explanation of the specific domain functions, mechanisms of ligand-receptor interaction, and mechanism of action of experimental drugs, see text.