Abstract
Abstract Efficient induction of cell death is essential for efficacy of cancer therapies, and may be enhanced in combination therapies that promote apoptosis. Small molecule mimetics of the pro-apoptotic protein SMAC antagonize Inhibitor of Apoptosis Proteins (IAPs). Debio 1143 is a potent oral SMAC mimetic currently assessed in clinical trials in combination with chemo- and radiotherapy in different cancer indications. We have conducted a “one vs. many” drug combination screen in which Debio 1143 is combined pairwise with a panel of 128 candidate partner agents in order to identify drug combinations that inhibit growth of lung adenocarcinoma cells. Several synergistic Debio 1143 combinations were selected for further analysis. We confirmed that Debio 1143 synergistically inhibited growth in combination with taxanes paclitaxel and docetaxel, topoisomerase inhibitor SN-38, and the bromodomain inhibitor JQ1. The combination of Debio 1143 with any of these agents further inhibited clonogenic colony formation and induced apoptosis more than either agent alone. In two Debio 1143-sensitive cell lines Debio 1143 also induced formation of the cell-death inducing complex - the ripoptosome. Interestingly, while Debio 1143 broadly reduced protein levels of cIAP1 across cell lines, specifically the combination with JQ1 also reduced cIAP2 and XIAP levels and inhibited the canonical NF-κB pathway while inducing the non-canonical NF-κB pathway. Overall, these data support utility of several combinations of Debio 1143 with other agents, especially bromodomain inhibitors, in lung adenocarcinoma and other cancers. Specifically, these findings indicate that the synergy between JQ1 and Debio 1143 may derive from JQ1 contributing on different levels to key mechanisms relevant for SMAC mimetic antitumor activity. Citation Format: Casey G. Langdon, Norbert Wiedemann, Matthew A. Held, James T. Platt, Ramanaiah Mamillapalli, Pinar Iyidogan, Nicholas Theodosakis, Frederic Levy, Denis Robichon, Claudio Zanna, Gregoire Vuagniaux, Mel Sorensen, Shaomeng Wang, Marcus W. Bosenberg, David F. Stern. Debio 1143 synergizes with taxanes, topoisomerase and bromodomain inhibitors to inhibit growth of lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2529. doi:10.1158/1538-7445.AM2015-2529
Published Version
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