Abstract
Abstract Navitoclax (formerly ABT-263) is a small molecule that potently antagonizes the activity of Bcl-2, Bcl-xL, and Bcl-w. To determine the potential of this molecule in combination with taxane-based chemotherapy, we evaluated a panel of 33 human NSCLC cell lines with a dose matrix of paclitaxel and navitoclax. All cell lines exhibited a greater than additive response to the combination, suggesting a synergistic interaction. These results were extended to mouse xenograft tumor models, in which the combination was more efficacious than either single agent docetaxel or navitoclax. Live cell time-lapse microscopy was used to demonstrate that the 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-xL and Mcl-1 correlate with the extent of synergy as measured by a Bliss independence model, suggesting that cancers with high levels of Bcl-xL will be relatively resistant to taxane-based therapy, but could benefit from addition of navitoclax to taxane treatment. Finally, a significant percentage of NSCLC patient samples exhibit high Bcl-xL levels, indicating the potential for broad utility of this combination in lung cancer.
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