Targeting the c-Met signaling pathway in cancer.
On binding to the cell surface receptor tyrosine kinase (TK) known as c-Met, hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of cellular targets including, epithelial and endothelial cells, hematopoietic cells, neurons, melanocytes, and hepatocytes. These pleiotropic actions are fundamentally important during development, homeostasis, and tissue regeneration. HGF signaling also contributes to oncogenesis and tumor progression in several human cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. Our present understanding of c-Met oncogenic signaling supports at least three avenues of pathway selective anticancer drug development: antagonism of ligand/receptor interaction, inhibition of TK catalytic activity, and blockade of intracellular receptor/effector interactions. Potent and selective preclinical drug candidates have been developed using all three strategies, and human clinical trials in two of the three areas are now under way.
Peruzzi
Benedetta
B
Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Bottaro
Donald P
DP
D000970:Antineoplastic Agents / Q000627:therapeutic use; D002227:Carbazoles / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D026121:Indole Alkaloids; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; C049985:staurosporine aglycone; D019859:Proto-Oncogene Proteins c-met