Abstract A16: A drug combination screen identifies taxanes as synergistic agents with the oral IAP inhibitor Debio 1143 in non-small cell lung cancer cells.

Abstract

Abstract Background: Drug resistance is a major problem in cancer therapy. The combination of drugs targeting simultaneously multiple critical nodes of the signalling networks controlling growth and survival of cancer cells is necessary to achieve long-lasting responses. The members of the Inhibitor of apoptosis protein (IAP) family are key negative regulators of programmed cell death. Their frequent overexpression in most cancer types contributes to tumor cell survival and resistance to cancer therapy making IAPs attractive therapeutic targets. The oral monovalent SMAC mimetic, Debio 1143/AT-406, functions as an antagonist of multiple IAP proteins (cIAP1/2 and XIAP) and is currently in clinical development for cancer treatment. The goal of this study is to identify novel synergistic combination partners with Debio 1143 in non-small cell lung cancer (NSCLC). Material and Methods: An in vitro high-throughput combination screen was performed using 6 human NSCLC cell lines bearing various genetic alterations. Debio 1143 was pairwise combined with 128 commercially available oncology compounds in a cell viability assay. To identify supra-additive drug combinations, the dose-response curves were analysed using the Bliss independence method. Synergistic combinations were further studied using tumor xenograft mouse models. Results: Among several interesting combinations, we observed strong synergism of Debio 1143 combined with docetaxel or paclitaxel, two standard-of-care drugs in NSCLC. The beneficial effect of the combination between Debio 1143 and taxanes was further validated in multiple mouse cancer xenografts where the combination caused marked anti-tumour activity that was superior to either monotherapy. Conclusion: These findings underline the feasibility of using in vitro high-throughput screening for the discovery of novel drug combinations with increased anti-tumour efficacy in vivo. Furthermore, they provide a rationale for the combination of the SMAC mimetic Debio 1143 with taxanes and are the basis for ongoing clinical trials in several cancer types. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A16. Citation Format: Casey G. Langdon, Norbert Wiedemann, Mathew A. Held, James T. Platt, Frédéric Lévy, Claudio Zanna, Grégoire Vuagniaux, Mel Sorensen, Shaomeng Wang, Marcus W. Bosenberg, David F. Stern. A drug combination screen identifies taxanes as synergistic agents with the oral IAP inhibitor Debio 1143 in non-small cell lung cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A16.