Abstract
To examine the potential of combining Bcl-2 family inhibitors with chemotherapy in ovarian cancer, we evaluated a panel of 27 ovarian cancer cell lines for response to the combination of navitoclax (formerly ABT-263) and paclitaxel or gemcitabine. The majority of cell lines exhibited a greater than additive response to either combination, as determined by the Bliss independence model, and more than 50% of the ovarian cell lines exhibited strong synergy for the navitoclax/paclitaxel combination. To identify biomarkers for tumors likely to respond to this combination, we evaluated the protein levels of intrinsic apoptosis pathway components. Bcl-x(L) seems necessary, but not sufficient, for navitoclax/paclitaxel synergy in vitro, suggesting that exclusion of patients whose tumors have low or undetectable Bcl-x(L) would enrich for patients responsive to the combination. We evaluated Bcl-x(L) levels in ovarian cancer tumor tissue from 40 patients (20 taxane responsive and 20 with poor response to taxane) and found that patients with high Bcl-x(L) were less sensitive to taxane treatment (10 of 12) Bcl-x(L) positive patients, P = 0.014). These data support the use of navitoclax in combination with taxane-based therapy in ovarian cancer patients with high levels of Bcl-x(L).
Highlights
Ovarian cancer is a major health concern
Most ovarian cancer cell lines exhibit a synergistic response to the combination of navitoclax and chemotherapy agents
To determine the potential of navitoclax to enhance the activity of these chemotherapies, we evaluated synergy with gemcitabine or paclitaxel in a panel of 27 ovarian cancer cell lines
Summary
Ovarian cancer is a major health concern. There have been improvements in the treatment of ovarian cancer, it is the sixth most frequent cause of cancer-related death in developed countries. Carboplatin is the mainstay of chemotherapy for ovarian cancer, and addition of either paclitaxel or gemcitabine to carboplatin significantly improves response. 75% of ovarian cancer patients respond to frontline therapy of debulking surgery followed by platinum-based therapy, most will experience recurrence [2]. There is a need for strategies to improve the durability of response to chemotherapy in ovarian cancer. One strategy is to combine chemotherapy with an inhibitor of antiapoptotic Bcl-2 family proteins to increase cell death after cell-cycle arrest [3, 4]
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