Abstract
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. 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. 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. 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).
Highlights
Taxane-based cancer therapy regimens, which are broadly used in the treatment of non–small cell lung cancer (NSCLC), yield overall response rates of 20% to 30% [2]
We show that non–small cell lung cancer (NSCLC) models with relatively high levels of Bcl-xL are more likely to show a synergistic response to the combination of a taxane and navitoclax and that 30% of NSCLC tumors express high levels of Bcl-xL by immunohistochemistry
Effects of navitoclax and paclitaxel in cultured cells Fifty-one human NSCLC cell lines were treated with navitoclax and paclitaxel in a 5 Â 5 dose matrix, and the combination effect was evaluated using the Bliss independence model
Summary
Taxane-based cancer therapy regimens, which are broadly used in the treatment of non–small cell lung cancer (NSCLC), yield overall response rates of 20% to 30% [2]. Taxanes, which include paclitaxel and docetaxel (DTX), bind and stabilize microtubules, causing cells to arrest in mitosis, and result in cytostatic or cytotoxic responses. Most studies of mechanisms of resistance to taxanes have focused on modulation of microtubule dynamics or the activity of efflux pumps such as P-gp [3]. The first described mechanism of resistance to taxanes was increased expression of efflux pumps. Authors' Affiliations: Departments of 1Research Oncology, 2Bio-informatics, and 3Protein Engineering, Genentech Inc., South San Francisco, California. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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