Activity of the multikinase inhibitor dasatinib against ovarian cancer cells.
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.
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90404-2429, USA. gkonecny@mednet.ucla.edu
G E
GE
Konecny
R
R
Glas
J
J
Dering
K
K
Manivong
J
J
Qi
R S
RS
Finn
G R
GR
Yang
K-L
KL
Hong
C
C
Ginther
B
B
Winterhoff
G
G
Gao
J
J
Brugge
D J
DJ
Slamon
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000069439:Dasatinib; D005260:Female; D005434:Flow Cytometry; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D020128:Inhibitory Concentration 50; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051575:Proto-Oncogene Proteins c-yes / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D036104:Receptor, EphA2; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051575:Proto-Oncogene Proteins c-yes; C489834:YES1 protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D000069439:Dasatinib