Abstract
Abstract The anti-apoptotic protein, BclXL, is thought to be an important chemo-resistance factor (Amundsen et al, 2000), and the combination of a BclXL inhibitor and paclitaxel exhibits increased NSCLC cancer cell killing in culture and in xenograft models (Shoemaker et al, 2006). ABT263 is a small molecule inhibitor of Bcl-2, BclXL and Bcl-w, that is currently in clinical trials (Tse et al, 2008). We set out to address the following questions 1) is ABT-263 broadly synergistic with paclitaxel in NSCLC cells, 2) what is the mechanism of the synergistic interaction and 3) can we identify biomarkers to guide the selection of patients that are likely to respond to the combination of ABT263 and taxane based chemotherapy regimens? We screened a panel of 26 NSCLC cell lines for synergy with ABT263. All 26 cell lines exhibited a synergistic response to the combination, as evaluated by Bliss additivity, and 20 cell lines had Bliss sum values in excess of 100, considered to be a robust synergy response in this assay. In order to address the mechanism of synergy, we performed time-lapse microscopy on GFP-H2b expressing A549 cells. We find that the addition of ABT263 alters the timing and fate of cells that enter mitosis in the presence of paclitaxel. Paclitaxel alone caused prolonged mitotic arrest usually followed by mitotic slippage. ABT263 as a single agent had little effect on mitosis, but caused cells to die rapidly from a mitotic arrest state when added to paclitaxel. This resulted in an increase in the rate and percentage of cell death compared to either single agent. To identify biomarkers that might influence synergy between ABT263 and paclitaxel, we identified genes whose mRNA levels had significant correlations with the Bliss score. Together these data suggest that the combination of ABT263 and paclitaxel has the potential to have improved efficacy in cancers that are refractory to paclitaxel. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A73.
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