BMS-777607, a small-molecule met kinase inhibitor, suppresses hepatocyte growth factor-stimulated prostate cancer metastatic phenotype in vitro.
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.
Dai
Yao
Y
Department of Radiation Oncology, University of Florida, Cancer Genetic Research Complex, Room 485E, Gainesville, Florida 32610, USA. daiyao@ufl.edu
Siemann
Dietmar W
DW
D000631:Aminopyridines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*
D000631:Aminopyridines; C550356:N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D054852:Small Molecule Libraries; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D048049:Extracellular Signal-Regulated MAP Kinases