Impact of the small molecule Met inhibitor BMS-777607 on the metastatic process in a rodent tumor model with constitutive c-Met activation

Clin Exp Metastasis. 2012 Mar;29(3):253-61. doi: 10.1007/s10585-011-9447-z.

Abstract

c-Met tyrosine kinase hyperactivation is strongly associated with tumor metastasis. In a prior study we showed that BMS-777607, a novel selective small molecule Met kinase inhibitor, potently suppressed ligand-mediated functions in prostate cancer cells. Herein we evaluated the impact of this agent on the potential of the highly metastatic murine KHT sarcoma that carries constitutive activated c-Met. MET gene knockdown was found to reduce spontaneous cell scatter and motility, suggesting a c-Met-dependent disseminating ability in KHT cells. Furthermore, BMS-777607 treatment potently inhibited KHT cell scatter, motility and invasion at doses in the nanomolar range. In contrast, cell proliferation and clonogenicity were modestly affected by BMS-777607. At the molecular level, BMS-777607 potently blocked phosphorylation of c-Met and downstream pathways over the same dose range that impacted metastasis-associated cell functions. In vivo, daily treatment with BMS-777607 (25 mg/kg/day) over the course of the study significantly decreased the number of KHT lung tumor nodules (28.3 ± 14.9%, P < 0.001) without apparent systemic toxicity. While treatment for short intervals (day 1 or 4) clearly reduced the foci number, delaying the initiation of BMS-777607 treatment until 8 days after tumor cell injection failed to show any reduction, implying that impairment of the initiation phases of the secondary growth via c-Met targeting is required to constrain the formation of macroscopic metastases. Together, the present findings demonstrate that the disruption of c-Met signaling by BMS-777607 significantly impairs the metastatic phenotype, suggesting that this agent may have therapeutic utility in targeting cancer metastasis.

MeSH terms

  • Aminopyridines / pharmacology
  • Aminopyridines / therapeutic use*
  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Humans
  • Mice
  • Mice, Inbred C3H
  • Neoplasm Invasiveness
  • Neoplasm Metastasis / prevention & control*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Pyridones / pharmacology
  • Pyridones / therapeutic use*
  • Sarcoma, Experimental / drug therapy*
  • Sarcoma, Experimental / pathology
  • Signal Transduction / drug effects

Substances

  • Aminopyridines
  • N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
  • Pyridones
  • Proto-Oncogene Proteins c-met