Dasatinib (BMS-35482) has synergistic activity with paclitaxel and carboplatin in ovarian cancer cells

Purpose. To explore the activity of dasatinib alone and in combination with paclitaxel and carboplatin in ovarian cancer cells and to determine if dasatinib activity can be predicted based on evaluation of the SRC pathway. Experimental design. Micrearray analysis was performed for IGROV1, OVCAR3, A2780 and SKOV3 ovarian cancer cells and the status of the genomic SRC signature pathway was determined. Cells were treated with carboplatin, paclitaxel and dasatinib individually and in combination. Pre- and post-treatment phospho-SRC (pSRC) and SRC protein expression was determined. Dose-response curves were constructed, and drug interaction was assessed by the Combination Index (CI) method. Results. SRC protein expression levels reflected the SRC pathway genomic signature in the cell lines with the lowest (SKOV3) and highest (IGROV1) pathway expression, but not in those with intermediate expression (OVCAR3, A2780). Dasatinib treatment caused loss of pSRC in all cell lines, with 50% growth inhibition for IGROV1 at 70 nM, OVCAR3 at 34 nM, A2780 at 4.1 mu M and SKOV3 at 530 nM. Dasatinib combined with cytotoxics yielded a synergistic effect (CI = 0.46 to 0.79) in all cell lines except SKOV3. Conclusion. Dasatinib in combination with standard chemotherapeutic agents appears to interact in a synergistic manner in some ovarian cancer cell lines. Further research is needed to evaluate tumor cell characteristics which predict response to dasatinib. (C) 2010 Elsevier Inc. All rights reserved.