C-Met

Overview
c-Met (Mesenchymal epithelial transition factor) is a proto-oncogene that encodes for a tyrosine kinase membrane receptor for hepatocyte growth factor/scatter factor (HGF/SF).

Fields of HGF/c-Met involvement
The c-Met protein is expressed mostly in epithelial cells, but also in endothelial cells, neural cells, hepatocytes, hematopoietic cells, melanocytes. c-Met might well be one of the most important membrane receptors. Its activation plays a key role in cellular physiology : mitogenesis, motogenesis, morphogenesis. HGF/SF seems essentially produced by cells of mesenchymal origin.

HGF/c-Met and Cancer
When HGF/SF activates c-Met, the first proteins to be activated downstream are Grb2 (growth factor receptor bound protein 2) and Gab 1 (growth factor receptor bound protein 2 associated binder 1). Grb2 in turn may activate a number of kinase pathways, including the pathway from Ras to Raf to Mek and to MAPK(mitogen-activated protein kinase). Gab 1 activates PI3K (phosphoinositide 3 kinase), which activates STAT3 (signal transducer and activator of transcription). c-Met activation also induces activation of beta catenin, a key component of the wnt pathway, which translocates into the nucleus and participates in transcription regulation.

The HGF/c-Met pathway plays an important role in the development of cancer. First through the activation of key oncogenic pathways (Ras, PI3K/STAT3, beta catenin), secondly through endothelial cell proliferation (neoangiogenesis), thirdly through increased protease production and hence cell dissociation leading to metastasis.

Cancer therapies targeting HGF/c-Met
Many new therapies,some of them in phase I or II clinical trials are aimed at the HGF/c-Met pathway :

- anti HGF monoclonal antibodies : a humanized one from AVEO (AV299), a fully human one from AMGEN (AMG102)

- truncated variants of c-Met that act as decoys : CGEN241 from COMPUGEN

- protein kinase inhibitors that block c-Met induced pathways : ARQ197 from ARQULE, XL880 from EXELIXIS, SGX523 from SGX Pharmaceuticals, MP470 from SUPERGEN, PF2341066 from PFIZER