Abstract 5441: Debio 1143, an oral antagonist of the inhibitor of apoptosis proteins, synergistically enhances the effects of multiple standard of care agents in human lung cancer models
Authors: Casey G. Langdon, Norbert Wiedemann, Mathew A. Held, James T. Platt, Frédéric Lévy, Denis Robichon, Claudio Zanna, Grégoire Vuagniaux, Mel Sorensen, Shaomeng Wang, Marcus W. Bosenberg, David F. Stern
Journal: Cancer Research (2014)

Abstract Background: Drug resistance is a major problem in cancer therapy that may be addressed by the combination of drugs simultaneously targeting multiple critical nodes of the signalling networks controlling growth and survival of cancer cells. The members of the Inhibitor of apoptosis protein (IAP) family are frequently overexpressed in most cancer types contributing to tumour cell survival and resistance to cancer therapy. The oral monovalent IAP inhibitor Debio 1143/AT-406 is currently in early clinical development. The aim of the study was to evaluate the activity of Debio 1143 as a single agent and in drug combinations in in vitro and in vivo lung cancer models of different histotypes. Materials and Methods: Drug sensitivity was assessed in clonogenic assays on 3-D cultures of patient-derived cancer xenografts of different lung histotypes. In vitro high-throughput combination screening (HTS) of 6 human lung adenocarcinoma cell lines was used to identify synergistic drug combinations for Debio 1143. Synergy was assessed using an AUC-based curve shift analysis method and selected synergistic combinations were further studied in tumour xenograft mouse models. Results: As a single agent Debio 1143 showed differential anti-proliferative activity in vitro in a majority of patient-derived cancer xenografts of small cell and squamous histology, whereas adenocarcinoma-derived samples were less responsive. However, HTS on 6 lung adenocarcinoma cell lines revealed synergy of Debio 1143 with several standard-of-care compounds. Synergy of the combination of Debio 1143 with docetaxel was further confirmed in vivo in mouse xenografts. Interestingly, while in vitro A549 cells were insensitive to Debio 1143 alone, a marked in vivo anti-tumour activity was observed on A549 xenografts. Conclusion: The IAP inhibitor Debio 1143 has single agent activity across 3D cultures of patient-derived xenografts of different lung cancer histotypes, as well as anti-tumour activity in NSCLC tumour xenograft mouse models. These findings provide a rationale for the combination of the IAP inhibitor Debio 1143 with standard-of-care compounds in different lung cancer histotypes and are the basis for ongoing clinical trials in several cancer types. Citation Format: Casey G. Langdon, Norbert Wiedemann, Mathew A. Held, James T. Platt, Frédéric Lévy, Denis Robichon, Claudio Zanna, Grégoire Vuagniaux, Mel Sorensen, Shaomeng Wang, Marcus W. Bosenberg, David F. Stern. Debio 1143, an oral antagonist of the inhibitor of apoptosis proteins, synergistically enhances the effects of multiple standard of care agents in human lung cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5441. doi:10.1158/1538-7445.AM2014-5441