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


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.


BMS-777607 c-Met Metastasis KHT Sarcoma 



Hepatocyte growth factor


Hepatocyte growth factor receptor


Phosphoinositide 3-kinases


Mammalian target of rapamycin


Mitogen-activated protein kinase


Extracellular-signal-regulated kinase


Focal adhesion kinase


Signal transducer and activator of transcription 3


S6 kinase


Fetal bovine serum



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)


  1. 1.
    Birchmeier C, Birchmeier W, Gherardi E et al (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4(12):915–925PubMedCrossRefGoogle Scholar
  2. 2.
    Comoglio PM, Giordano S, Trusolino L (2008) Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 7(6):504–516PubMedCrossRefGoogle Scholar
  3. 3.
    Danilkovitch-Miagkova A, Zbar B (2002) Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Investig 109(7):863–867PubMedGoogle Scholar
  4. 4.
    Maulik G, Shrikhande A, Kijima T et al (2002) Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev 13(1):41–59PubMedCrossRefGoogle Scholar
  5. 5.
    Eder JP, Vande Woude GF, Boerner SA et al (2009) Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res 15(7):2207–2214PubMedCrossRefGoogle Scholar
  6. 6.
    You WK, McDonald DM (2008) The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis. BMB Rep 41(12):833–839PubMedCrossRefGoogle Scholar
  7. 7.
    Boccaccio C, Comoglio PM (2006) Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat Rev Cancer 6(8):637–645PubMedCrossRefGoogle Scholar
  8. 8.
    Zhu H, Naujokas MA, Fixman ED et al (1994) Tyrosine 1356 in the carboxyl-terminal tail of the HGF/SF receptor is essential for the transduction of signals for cell motility and morphogenesis. J Biol Chem 269(47):29943–29948PubMedGoogle Scholar
  9. 9.
    Chen SY, Chen HC (2006) Direct interaction of focal adhesion kinase (FAK) with Met is required for FAK to promote hepatocyte growth factor-induced cell invasion. Mol Cell Biol 26(13):5155–5167PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang YW, Wang LM, Jove R et al (2002) Requirement of Stat3 signaling for HGF/SF-Met mediated tumorigenesis. Oncogene 21(2):217–226PubMedCrossRefGoogle Scholar
  11. 11.
    Migliore C, Giordano S (2008) Molecular cancer therapy: Can our expectation be MET? Eur J Cancer 44(5):641–651PubMedCrossRefGoogle Scholar
  12. 12.
    Stellrecht CM, Gandhi V (2009) MET receptor tyrosine kinase as a therapeutic anticancer target. Cancer Lett 280(1):1–14PubMedCrossRefGoogle Scholar
  13. 13.
    Goldberg J, Demetri GD, Choy E et al (2009) Preliminary results from a phase II study of ARQ 197 in patients with microphthalmia transcription factor family (MiT)-associated tumors. J Clin Oncol 27(15s):10502Google Scholar
  14. 14.
    Ross RW, Stein M, Sarantopoulos J et al (2007) A phase II study of the c-Met RTK inhibitor XL880 in patients (pts) with papillary renal-cell carcinoma (PRC). J Clin Oncol 25(18s):15601Google Scholar
  15. 15.
    Schiller JH, Akerley WL, Brugger W, et al. (2010) Results from ARQ 197-209: a global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 28(18s):(suppl; abstr LBA7502)Google Scholar
  16. 16.
    Schroeder GM, An Y, Cai ZW et al (2009) Discovery of N-(4-(2-amino-3-chloropyridine-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J Med Chem 52(5):1251–1254PubMedCrossRefGoogle Scholar
  17. 17.
    Christensen JG, Schreck R, Burrows J et al (2003) A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res 63(21):7345–7355PubMedGoogle Scholar
  18. 18.
    Buchanan SG, Hendle J, Lee PS et al (2009) SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. Mol Cancer Ther 8(12):3181–3190PubMedCrossRefGoogle Scholar
  19. 19.
    Dai Y, Siemann DW (2010) BMS-777607, a small-molecule met kinase inhibitor, suppresses hepatocyte growth factor-stimulated prostate cancer metastatic phenotype in vitro. Mol Cancer Ther 9(6):1554–1561PubMedCrossRefGoogle Scholar
  20. 20.
    Dong M, Rice L, Lepler S et al (2010) Impact of the Src inhibitor saracatinib on the metastatic phenotype of a fibrosarcoma (KHT) tumor model. Anticancer Res 30:4405–4414PubMedGoogle Scholar
  21. 21.
    Siemann DW (1995) Chemosensitization of CCNU in KHT murine tumor cells in vivo and in vitro by the agent RB 6145 and its isomer PD 144872. Radiother Oncol 34(1):47–53PubMedCrossRefGoogle Scholar
  22. 22.
    Rice L, Pampo C, Lepler S et al (2011) Support of a free radical mechanism for enhanced antitumor efficacy of the microtubule disruptor OXi4503. Microvasc Res 81:44–51PubMedCrossRefGoogle Scholar
  23. 23.
    Rosen EM, Nigam SK, Goldberg ID (1994) Scatter factor and the c-met receptor: a paradigm for mesenchymal/epithelial interaction. J Cell Biol 127(6 Pt 2):1783–1787PubMedCrossRefGoogle Scholar
  24. 24.
    Benvenuti S, Comoglio PM (2007) The MET receptor tyrosine kinase in invasion and metastasis. J Cell Physiol 213(2):316–325PubMedCrossRefGoogle Scholar
  25. 25.
    Lee JH, Han SU, Cho H et al (2000) A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene 19(43):4947–4953PubMedCrossRefGoogle Scholar
  26. 26.
    Ma PC, Tretiakova MS, MacKinnon AC et al (2008) Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer 47(12):1025–1037PubMedCrossRefGoogle Scholar
  27. 27.
    Lal B, Xia S, Abounader R et al (2005) Targeting the c-Met pathway potentiates glioblastoma responses to gamma-radiation. Clin Cancer Res 11(12):4479–4486PubMedCrossRefGoogle Scholar
  28. 28.
    Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG (2009) Targeting MET as a strategy to overcome crosstalk-related resistance to EGFR inhibitors. Lancet Oncol 10(7):709–717PubMedCrossRefGoogle Scholar
  29. 29.
    Ma PC, Tretiakova MS, Nallasura V et al (2007) Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion. Br J Cancer 97(3):368–377PubMedCrossRefGoogle Scholar
  30. 30.
    Tang Z, Du R, Jiang S et al (2008) Dual MET-EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer. Br J Cancer 99(6):911–922PubMedCrossRefGoogle Scholar
  31. 31.
    Liao AT, McCleese J, Kamerling S et al (2007) A novel small molecule Met inhibitor, PF2362376, exhibits biological activity against osteosarcoma. Vet Comp Oncol 5(3):177–196PubMedCrossRefGoogle Scholar
  32. 32.
    Zillhardt M, Christensen JG, Lengyel E (2010) An orally available small-molecule inhibitor of c-Met, PF-2341066, reduces tumor burden and metastasis in a preclinical model of ovarian cancer metastasis. Neoplasia 12(1):1–10PubMedGoogle Scholar
  33. 33.
    Cassinelli G, Lanzi C, Petrangolini G et al (2006) Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RPI-1. Mol Cancer Ther 5(9):2388–2397PubMedCrossRefGoogle Scholar
  34. 34.
    Munshi N, Jeay S, Li Y et al (2010) ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther 9(6):1544–1553PubMedCrossRefGoogle Scholar
  35. 35.
    Stoker M, Gherardi E, Perryman M et al (1987) Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327(6119):239–242PubMedCrossRefGoogle Scholar

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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