BMS-777607, a small-molecule met kinase inhibitor, suppresses hepatocyte growth factor-stimulated prostate cancer metastatic phenotype in vitro.

Abstract

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.

• Authors: Yao Dai, Dietmar W Siemann
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 6 Pg. 1554-61 (Jun 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 20515943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
• Protein Kinase Inhibitors
• Pyridones
• Small Molecule Libraries
• Hepatocyte Growth Factor
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-met
• Extracellular Signal-Regulated MAP Kinases

Topics

• Aminopyridines (pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Hepatocyte Growth Factor (pharmacology)
• Humans
• Male
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Phenotype
• Phosphatidylinositol 3-Kinases (metabolism)
• Prostatic Neoplasms (enzymology, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, metabolism)
• Pyridones (pharmacology)
• Signal Transduction (drug effects)
• Small Molecule Libraries (pharmacology)