c-Met/HGFR is the product of the MET gene, playing an important role in normal cellular function and oncogenesis. The biological activities triggered by binding of HGF to c-Met/HGFR, the product of the MET proto-oncogene, initiates a complex variety of responses. This is in part due to the expression of c-Met/HGFR on functionally different cells; its functions may include growth, transformation, cell motility, invasion, metastasis, epithelial to mesenchymal transition (EMT), angiogenesis, wound healing, or tissue regeneration depending on the cellular context Owing to the pleiotropic effects regulated through activated c-Met/HGFR and the variety of cells that express the receptor, it is not surprising that this pathway has gained interest as a driving force in tumor initiation, maintenance, and progression of not only lung cancer but also other malignancies.
There are two major mechanisms involving c-Met/HGFR that can lead to activation or hyperresponsiveness of the c-Met/HGFR-HGF pathway. MET can be either mutated in the extracellular or in the cytoplasmic domain. Mutations can alter inhibitory constraints that allow the kinase to be either active or hyperresponsive to stimuli. Mutations can also alter the degree of activation or prevent efficient degradation of the protein, therefore prolonging the duration of the biochemical signals. Another mechanism of ligand-independent activation is the overexpression of the functional wild-type protein.
Ongoing clinical trials will potentially validate c-Met/HGFR as a therapeutic target, improving the outcome of patients with c-Met/HGFR-dependent cancers. c-Met/HGFR small molecule inhibitors have been utilized as single agents as well as in combination regimens. Currently, phase I and II studies are ongoing to evaluate the monovalent antagonist antibody to MET (MetMAb; also known as onartuzumab).
c-Met/HGFR is involved in many mechanisms of cancer proliferation and metastasis. c-Met/HGFR overexpression and genetic alterations play a role in the pathogenesis of several tumors, including lung cancer. The recent development of c-Met/HGFR-targeted agents offers the potential for improving patient outcomes in malignant diseases.
Sattler M, et al. The role of the c-Met pathway in lung cancer and the potential for targeted therapy[J]. Therapeutic advances in medical oncology, 2011, 3(4): 171-184.