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

Abstract

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 Microarray 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 70nM, OVCAR3 at 34nM, A2780 at 4.1μM and SKOV3 at 530nM. 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.

Synergistic Anti-Tumor Effect of Cisplatin When Combined with an Anti-Src Kinase Integrin-Based Peptide

“…Accordingly, targeted therapy with the Src inhibitor dasatinib has been shown to interact in a synergistic manner with platinum-based chemotherapy in ovarian cancer cells [21]. A 15 mer peptide, RSKAKWQTGTNPLYR, representing the ERK2 binding sequence located within the β6 integrin tail has previously been reported to also inhibit c-Src activity [22].…”

“…However, there are no published data on comparative levels of c-Src expression or activity between the cisplatinsensitive A2780 cell line and the cisplatin-resistant subline ADDP. Cisplatin-sensitive A2780 cells are known to be high expressors of Src [21] and whether Src deregulation is further enhanced in A2780 cells with acquired resistance to cisplatin such as the ADDP subline is not known.…”

Dasatinib (BMS-35482) Interacts Synergistically With Docetaxel, Gemcitabine, Topotecan, and Doxorubicin in Ovarian Cancer Cells With High SRC Pathway Activation and Protein Expression

“…Total SRC (tSRC) protein expression by Western blot analysis demonstrated low relative SRC protein expression in SKOV3 (1.713) and A2780 (0.404) and high relative SRC expression in IGROV1 (2.27). 5 The relative expression of the SRC pathway signature on a scale from 0% to 100% was SKOV3 (38.3%), A2780 (55.1%), and IGROV1 (60.4%). 5 Evaluation of the SRC pathway was based on a previously defined SRC pathway gene signature.…”

“…5 The relative expression of the SRC pathway signature on a scale from 0% to 100% was SKOV3 (38.3%), A2780 (55.1%), and IGROV1 (60.4%). 5 Evaluation of the SRC pathway was based on a previously defined SRC pathway gene signature. 14 …”

“…5Y8 We previously demonstrated the synergistic activity of dasatinib in combination with paclitaxel and carboplatin in selected ovarian cancer cell lines. 5 Based on this data, we conducted a phase 1 trial of combination paclitaxel and carboplatin in women with advanced and recurrent epithelial ovarian, peritoneal, or tubal cancer. 9 We observed a response rate of 40% including 3 (15%) complete responses and 5 (25%) partial responses with stable disease in 10 (50%) patients.…”