Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

Br J Cancer. 2009 Nov 17;101(10):1699-708. doi: 10.1038/sj.bjc.6605381. Epub 2009 Oct 27.


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 micromol 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.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Dasatinib
  • Female
  • Flow Cytometry
  • Focal Adhesion Kinase 1 / antagonists & inhibitors
  • Focal Adhesion Kinase 1 / metabolism
  • Gene Expression Profiling
  • Humans
  • Inhibitory Concentration 50
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-yes / antagonists & inhibitors
  • Proto-Oncogene Proteins c-yes / metabolism
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology*
  • Receptor, EphA2 / antagonists & inhibitors
  • Receptor, EphA2 / metabolism
  • Thiazoles / administration & dosage
  • Thiazoles / pharmacology*
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism


  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiazoles
  • Receptor, EphA2
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Proto-Oncogene Proteins c-yes
  • YES1 protein, human
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • Dasatinib