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Clinical & Experimental Metastasis

, Volume 29, Issue 3, pp 253–261 | Cite as

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

  • Yao Dai
  • Kyungmi Bae
  • Christine Pampo
  • Dietmar W. Siemann
Research Paper

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.

Keywords

BMS-777607 c-Met Metastasis KHT Sarcoma 

Abbreviations

HGF

Hepatocyte growth factor

HGFR

Hepatocyte growth factor receptor

PI3K

Phosphoinositide 3-kinases

mTOR

Mammalian target of rapamycin

MAPK

Mitogen-activated protein kinase

ERK

Extracellular-signal-regulated kinase

FAK

Focal adhesion kinase

STAT3

Signal transducer and activator of transcription 3

S6K

S6 kinase

FBS

Fetal bovine serum

Notes

Acknowledgments

The authors acknowledge Sharon Lepler for technical assistance and Dr. Joseph Fargnoli (Bristol-Myer Squibb R&D) for scientific discussion.

Supplementary material

10585_2011_9447_MOESM1_ESM.ppt (310 kb)
Supplementary material 1 (PPT 307 kb)

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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Yao Dai
    • 1
  • Kyungmi Bae
    • 2
  • Christine Pampo
    • 1
  • Dietmar W. Siemann
    • 1
  1. 1.Department of Radiation OncologyUniversity of FloridaGainesvilleUSA
  2. 2.Department of UrologyShands Cancer Center at the University of FloridaGainesvilleUSA

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