SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells

// Casey G. Langdon 1,* , Norbert Wiedemann 2,* , Matthew A. Held 1,6 , Ramanaiah Mamillapalli 1 , Pinar Iyidogan 1 , Nicholas Theodosakis 1 , James T. Platt 1,3 , Frederic Levy 2 , Gregoire Vuagniaux 2 , Shaomeng Wang 5 , Marcus W. Bosenberg 1,4 and David F. Stern 1 1 Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA 2 Debiopharm International SA, Lausanne, Switzerland 3 Breast Medical Oncology Group, Yale Cancer Center, New Haven, CT, USA 4 Departments of Dermatology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA 5 Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA 6 Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA * These authors have contributed equally to this work Correspondence to: David F. Stern, email: // Keywords : SMAC mimetic, combination therapy, lung adenocarcinoma, high throughput screening, bromodomain inhibitor Received : September 25, 2015 Accepted : September 26, 2015 Published : October 16, 2015 Abstract Targeting anti-apoptotic proteins can sensitize tumor cells to conventional chemotherapies or other targeted agents. Antagonizing the Inhibitor of Apoptosis Proteins (IAPs) with mimetics of the pro-apoptotic protein SMAC is one such approach. We used sensitization compound screening to uncover possible agents with the potential to further sensitize lung adenocarcinoma cells to the SMAC mimetic Debio 1143. Several compounds in combination with Debio 1143, including taxanes, topoisomerase inhibitors, and bromodomain inhibitors, super-additively inhibited growth and clonogenicity of lung adenocarcinoma cells. Co-treatment with Debio 1143 and the bromodomain inhibitor JQ1 suppresses the expression of c-IAP1, c-IAP2, and XIAP. Non-canonical NF-κB signaling is also activated following Debio 1143 treatment, and Debio 1143 induces the formation of the ripoptosome in Debio 1143-sensitive cell lines. Sensitivity to Debio 1143 and JQ1 co-treatment was associated with baseline caspase-8 expression. In vivo treatment of lung adenocarcinoma xenografts with Debio 1143 in combination with JQ1 or docetaxel reduced tumor volume more than either single agent alone. As Debio 1143-containing combinations effectively inhibited both in vitro and in vivo growth of lung adenocarcinoma cells, these data provide a rationale for Debio 1143 combinations currently being evaluated in ongoing clinical trials and suggest potential utility of other combinations identified here.