Preclinical Development Navitoclax (ABT-263) Reduces Bcl-xL–Mediated Chemoresistance in Ovarian Cancer Models

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 ABT263) andpaclitaxel or gemcitabine. Themajority 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 theprotein levels of intrinsic apoptosis pathway components. Bcl-xL seems necessary, but not sufficient, for navitoclax/paclitaxel synergy in vitro, suggesting that exclusion of patients whose tumors have low or undetectable Bcl-xL would enrich for patients responsive to the combination.We evaluated Bcl-xL levels in ovarian cancer tumor tissue from 40patients (20 taxane responsive and 20 with poor response to taxane) and found that patients with high Bcl-xL were less sensitive to taxane treatment (10 of 12) Bcl-xL positive patients, P 1⁄4 0.014). These data support the use of navitoclax in combination with taxane-based therapy in ovarian cancer patients with high levels of Bcl-xL. Mol Cancer Ther; 11(4); 1026–35. 2012 AACR.