c-Met/HGFR was first identified in the early 1980s as the product of a chromosomal rearrangement after treatment with the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine. This rearrangement results in a constitutively fused oncogene, TPR-MET, which translates into an oncoprotein following dimerization by a leucine-zipper motif located in the TPR moiety. This provides the structural requirement for c-Met/HGFR kinase to be constitutively active. TPR-MET has the ability to transform epithelial cells, and to induce spontaneous mammary tumors when ubiquitously overexpressed in transgenic mice. These findings set the starting point for a currently ongoing effort to unveil all oncogenic abilities of c-Met/HGFR. It took more than a decade to provide the proof of concept for the role of c-Met/HGFR in human cancers, which became evident following the identification of activating point mutations in the germline of patients affected by hereditary papillary renal carcinomas. However, spontaneously occurring oncogenic MET mutations remain rare at 2 3%. A large number of reports have shown that an altered level of RTK activation can play an important role in the pathophysiology of cancer. Deregulation and the consequent aberrant signaling of c-Met/HGFR may occur by different mechanisms including gene amplification, overexpression, activating mutations, increased autocrine or paracrine ligand-mediated stimulation, and interaction with other active cell-surface receptors. Many studies have reported that c-Met/HGFR is overexpressed in a variety of carcinomas including lung, breast, ovary, kidney, colon, thyroid, liver, and gastric carcinomas. Such overexpression could be the result of transcriptional activation, hypoxia-induced overexpression, or as a result of MET amplification, which is notably observed only in a small subset of cancers. Transgenic mice overexpressing c-Met/HGFR have been reported to spontaneously develop hepatocellular carcinoma, and when the transgene was inactivated, tumor regression was reported even in large tumors. Because of its pleotrophic role in cellular processes important in oncogenesis and cancer progression, c-Met/HGFR is considered to be an important target in anticancer therapy. Several molecules targeting c-Met/HGFR have recently been evaluated in early phase clinical trials. Most of them are small kinase inhibitors, while some are biological antagonists and monoclonal antibodies targeting either the ligand or the receptor.
Drug targets for cancer: c-Met/HGFR research reagents
Other vital drug targets for cancer likec-Met/HGFR:
Sierra J R, Tsao M S. c-MET as a potential therapeutic target and biomarker in cancer[J]. Therapeutic advances in medical oncology, 2011, 3(1 suppl): S21-S35.