title: Impact of the small molecule Met inhibitor BMS-777607 on the metastatic process in a rodent tumor model with constitutive c-Met activation.
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.
authors.affiliation: Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA. daiyao@ufl.edu
authors.forename: Yao
authors.initials: Y
authors.lastname: Dai
authors.forename: Kyungmi
authors.initials: K
authors.lastname: Bae
authors.forename: Christine
authors.initials: C
authors.lastname: Pampo
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Siemann
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: 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; D011728:Pyridones; D019859:Proto-Oncogene Proteins c-met