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Ref Type Journal Article
PMID (20515943)
Authors Dai Y, Siemann DW
Title BMS-777607, a small-molecule met kinase inhibitor, suppresses hepatocyte growth factor-stimulated prostate cancer metastatic phenotype in vitro.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 9 6 2010 Jun 1554-61 Mol Cancer Ther
URL
Abstract Text Most prostate cancer-related deaths are due to advanced disease with patients with metastatic prostate cancer having a 5-year survival rate of only 34%. Overexpression of c-Met receptor tyrosine kinase has been highly associated with prostate cancer progression and metastasis. In the present studies, the effect of BMS-777607, a selective and potent small-molecule Met kinase inhibitor that has been advanced to clinical evaluation, on hepatocyte growth factor (HGF)-mediated cell functions and signaling pathways was evaluated in c-Met-expressing PC-3 and DU145 prostate cancer cells. BMS-777607 treatment had little effect on tumor cell growth but inhibited cell scattering activated by exogenous HGF, with almost complete inhibition at 0.5 micromol/L in PC-3 and DU145 cells. This agent also suppressed HGF-stimulated cell migration and invasion in a dose-dependent fashion (IC(50) < 0.1 micromol/L) in both cell lines. Mechanistically, nanomolar doses of BMS-777607 potently blocked HGF-stimulated c-Met autophosphorylation and downstream activation of Akt and extracellular signal-regulated kinase. In addition, both wortmannin and U0126, but not dasatinib, attenuated cell scattering and migration induced by HGF, suggesting the involvement of the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways, but not of Src or focal adhesion kinase, in HGF-mediated motogenic effects. Taken together, these data indicate that the downregulation of c-Met signaling by BMS-777607 treatment can significantly disrupt key steps in the metastatic cascade, suggesting that such a targeting strategy may hold promise for the treatment of advanced prostate cancer.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
BMS-777607 BMS-777607 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
BMS-777607 ASLAN002 AXL Inhibitor 30 MET Inhibitor 59 RON Inhibitor 11 TYRO3 Inhibitor 8 BMS-777607 (ASLAN002) is a small molecule that inhibits MET, MST1R (RON), TYRO3, and AXL, resulting in decreased downstream pathway activation, potentially resulting in decreased tumor cell growth and metastasis (PMID: 19260711, PMID: 20515943, PMID: 24233399, PMID: 26555154).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References