Abstract
The c-MET receptor tyrosine kinase plays important roles in the formation, progression, and dissemination of human cancer and presents an attractive therapeutic target. This study describes the preclinical characterization of INCB28060, a novel inhibitor of c-MET kinase. Studies were conducted using a series of in vitro and in vivo biochemical and biological experiments. INCB28060 exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10,000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET-dependent tumor cell lines. As a result, INCB28060 potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. Oral dosing of INCB28060 results in time- and dose-dependent inhibition of c-MET phosphorylation and tumor growth in c-MET-driven mouse tumor models, and the inhibitor is well tolerated at doses that achieve complete tumor inhibition. In a further exploration of potential interactions between c-MET and other signaling pathways, we found that activated c-MET positively regulates the activity of epidermal growth factor receptors (EGFR) and HER-3, as well as expression of their ligands. These effects are reversed with INCB28060 treatment. Finally, we confirmed that circulating hepatocyte growth factor levels are significantly elevated in patients with various cancers. Activated c-MET has pleiotropic effects on multiple cancer-promoting signaling pathways and may play a critical role in driving tumor cell growth and survival. INCB28060 is a potent and selective c-MET kinase inhibitor that may have therapeutic potential in cancer treatment.
Highlights
Introduction cMET, originally identified as a TRP–MET fusion gene from a human osteosarcoma cell line, encodes a prototype member of a distinct subfamily of heterodimeric receptor tyrosine kinases (RTK; ref. 1)
C-MET and Hepatocyte growth factor (HGF) are present in many different tissues, their expression is mainly confined to cells of epithelial and mesenchymal origins, respectively
In exploring potential cross-talk between c-MET and epidermal growth factor receptors (EGFR)/HER-3, we find that c-MET upregulates the activity of EGFR and HER-3 directly through these receptors or by stimulating their ligand production, and these effects can be reversed by INCB28060
Summary
Introduction cMET, originally identified as a TRP–MET fusion gene from a human osteosarcoma cell line, encodes a prototype member of a distinct subfamily of heterodimeric receptor tyrosine kinases (RTK; ref. 1). MET, originally identified as a TRP–MET fusion gene from a human osteosarcoma cell line, encodes a prototype member of a distinct subfamily of heterodimeric receptor tyrosine kinases Hepatocyte growth factor (HGF) is the only known high affinity ligand for the c-MET receptor. Binding of HGF to c-MET causes receptor multimerization, phosphorylation, and catalytic activation. Author's Affiliation: Incyte Corporation, Wilmington, Delaware (GRB2)-associated binding protein], GRB2, SHC (Src homology and collagen), and c-Cbl and leads to activation of multiple downstream effector pathways or proteins, including RAS/MAPK (mitogen-activated protein kinase), PI3K (phosphoinositide-3-kinase)/AKT, FAK (focal adhesion kinase), STAT3/5, RAC/RHO, PLC-g (phospholipase Cg), c-SRC, SHP2 (a Src homology 2-containing tyrosine phosphatase), and CRKL, that are essential for regulating cell growth, survival, motility, invasion, and cytoskeletal changes [1, 2]. C-MET and HGF are present in many different tissues, their expression is mainly confined to cells of epithelial and mesenchymal origins, respectively. The evidence that links c-MET directly to cancer arose from the original discovery of missense c-MET mutations in all patients with hereditary www.aacrjournals.org
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