Abstract 2700: The IAP inhibitor Debio 1143 reverses carboplatin resistance in ovarian cancer cells by inducing both apoptosis and necroptosis

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Ovarian cancer remains the most lethal gynecological cancer. The efficacy of conventional chemotherapy with a combination of platinum salts and taxanes is transient because 70 to 80% of patients initially responding to platinum finally relapse. Mechanisms of resistance to carboplatin include a disruption of the balance between key pro-and anti-apoptotic proteins such as the inhibitor of apoptosis protein (IAP) family. Drug mimetics of the endogenous IAP inhibitor SMAC constitute a novel therapeutic approach to overcome apoptosis resistance and are currently in clinical development for cancer treatment. In this study we tested the ability of the oral IAP inhibitor Debio 1143 to revert carboplatin resistance in three carboplatin-sensitive (OVCAR-3, IGROV-1, A2780S) and three carboplatin-resistant (SKOV-3, A2780R, EFO-21) human ovarian tumor cell lines. We demonstrated that in vitro Debio 1143 was able to sensitize SKOV-3, EFO-21 and A2780R ovarian tumor cells to carboplatin. In addition, we demonstrated that the combination allowed a full recovery of carboplatin sensitivity in A2780R similar to the sensitive cell line A2780S. The sensitization to carboplatin correlated with an increased induction of apoptosis (Annexin V/PI assay and PARP cleavage) in SKOV-3 and A2780R cells. In EFO-21 cells, Debio 1143 triggered necroptosis as shown by the necroptosis inhibitor necrostatin-1 which was able to suppress Debio 1143-induced cell death with or without carboplatin. Our study shows that in the above human ovarian tumor cell lines Debio 1143 induces degradation of cIAP1 while XIAP levels remain unchanged. Using a carboplatin-resistant in vivo ovarian tumor mouse model, we further showed that Debio 1143 alone or in combination with carboplatin causes marked regression of subcutaneous SKOV-3 tumors. Together, our results suggest that Debio 1143 in combination with carboplatin could provide considerable benefit to patients with innate or acquired resistance to carboplatin by acting as a sensitizing agent. Debio 1143 is currently evaluated in combination with carboplatin and paclitaxel in patient with advanced solid malignancies including platinum-refractory ovarian cancer ([NCT01930292][1]). Citation Format: Benoit Thibault, Ludivine Genre, Clothilde Broca, Maryse Barbier, Claudio Zanna, Gregoire Vuagniaux, Jean-Pierre Delord, Bettina Couderc. The IAP inhibitor Debio 1143 reverses carboplatin resistance in ovarian cancer cells by inducing both apoptosis and necroptosis. [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 2700. doi:10.1158/1538-7445.AM2015-2700 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01930292&atom=%2Fcanres%2F75%2F15_Supplement%2F2700.atom