Navitoclax (ABT-263) Reduces Bcl-xL Mediated Chemo-resistance in Ovarian Cancer Models
Menée sur 27 lignées cellulaires de cancer ovarien et des échantillons tumoraux prélevés sur 40 patientes, cette étude évalue l'activité antitumorale du navitoclax, un inhibiteur de Bcl-2, en combinaison avec du paclitaxel ou de la gemcitabine
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-xL appears 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 40 patients (20 taxane responsive and 20 with poor response to taxane), and found that patients with high Bcl-xL were less sensitive to taxane treatment (10/12) Bcl-xL 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-xL.
http://mct.aacrjournals.org/content/early/2012/02/01/1535-7163.MCT-11-0693.abstract