Navitoclax Enhances the Efficacy of Taxanes in Non–Small Cell Lung Cancer Models

Abstract

Purpose: To explore the potential of navitoclax in combination with taxane-based chemotherapy in the treatment of non–small cell lung cancer (NSCLC) by defining mechanism of synergy and identifying correlative biomarkers.

Experimental Design: We treated a panel of NSCLC lines with a dose matrix of paclitaxel and navitoclax (formerly ABT-263), an inhibitor of Bcl-2, Bcl-x_L, and Bcl-w (1), and evaluated synergy. We next used time-lapse microscopy to explore mechanism of synergy. Finally, we developed an immunohistochemical assay and assessed prevalence of Bcl-x_L in NSCLC tumor tissues.

Results: All cell lines exhibit greater than additive response to the combination of navitoclax and a taxane. These results were extended to mouse xenograft tumor models, in which the combination is more efficacious than either single-agent docetaxel or navitoclax. Addition of navitoclax to paclitaxel decreases the time from mitotic entry to cell death and changes cell fate from mitotic slippage to death during mitotic arrest. The relative levels of Bcl-x_L and Mcl-1 correlate with the extent of synergy, suggesting that cancers with elevated levels of Bcl-x_L will be relatively resistant to taxane-based therapy but could benefit from the addition of navitoclax to taxane treatment. Finally, a significant percentage of NSCLC patient samples exhibit relatively high Bcl-x_L levels.

Conclusions: The addition of navitoclax to taxane-based chemotherapy in NSCLC has the potential to increase efficacy, particularly in patients whose tumors express high levels of Bcl-x_L. Clin Cancer Res; 17(6); 1394–404. ©2011 AACR.