Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

G. E. Konecny, R. Glas, J. Dering, K. Manivong, J. Qi, R. S. Finn, G. R. Yang, K. L. Hong, C. Ginther, B. Winterhoff, G. Gao, J. Brugge, D. J. Slamon

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Background:Here, we explore the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, including members of the Src kinase family, EphA2, and focal adhesion kinase for the treatment of ovarian cancer.Methods:We examined the effects of dasatinib on proliferation, invasion, apoptosis, cell-cycle arrest, and kinase activity using a panel of 34 established human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions with chemotherapeutic drugs.Results:Concentration-dependent anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC 50 values (IC 50 range: 0.001-11.3 mol l 1). Dasatinib significantly inhibited invasion, and induced cell apoptosis, but less cell-cycle arrest. At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin (mean CI values, range: 0.73-1.11) or paclitaxel (mean CI values, range: 0.76-1.05). In this study, 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive to dasatinib, compared with only 8 out of 39 (21%) representative breast cancer cell lines previously reported. Cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1, and uPA were particularly sensitive to dasatinib.Conclusions:These data provide a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer.

Original languageEnglish (US)
Pages (from-to)1699-1708
Number of pages10
JournalBritish Journal of Cancer
Volume101
Issue number10
DOIs
StatePublished - Nov 2009

Keywords

  • Dasatinib
  • Eph2A
  • FAK
  • Ovarian cancer
  • Src
  • UPA

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