Abstract 3967: Potent treatment combinations with CIB1 depletion in triple-negative breast cancer

Abstract The current standard of care for triple-negative breast cancer (TNBC) patients is limited to chemotherapy, radiation, and/or surgery. Therefore, there is a pressing need for new targeted therapies to improve clinical efficacy, reduce toxicity, and overcome resistance. We previously found that CIB1 depletion induces cell death selectively in TNBC cells, while sparing normal cells. The purpose of this study was to ask whether depleting CIB1 further enhances tumor-specific killing when combined with either the commonly used chemotherapeutic, docetaxel, or the cell death-inducing ligand, TRAIL. To address this, we targeted CIB1 by RNA interference in MDA-MB-436, MDA-MB-231, MDA-MB-468 TNBC cells and ME16C normal breast epithelial cells alone or combination with docetaxel or TRAIL. Cell death was quantified via trypan blue exclusion using FACS and cell death mechanisms were analyzed by Western blotting. We found that the combination of CIB1 depletion with docetaxel significantly enhanced tumor-specific cell death relative to each treatment alone. The enhanced cell death strongly correlated with caspase-8 activation, a hallmark of death receptor-mediated apoptosis. Because CIB1 depletion also upregulated the death receptor, TRAIL-R2, we tested for sensitization to TRAIL. While TRAIL alone had no effect on cell viability, CIB1 depletion profoundly sensitized tumor cells to TRAIL, resulting in a synergistic increase in cell death. In addition to death receptor-mediated apoptosis, both combination treatments activated a non-apoptotic mechanism, called paraptosis. Interestingly, these combination treatments also induced nearly complete death of docetaxel-resistant MDA-MB-436 cells, again via apoptosis and paraptosis. In contrast, neither combination treatment induced cell death in normal ME16C cells. In conclusion, our results demonstrate that the novel combinations of CIB1 depletion with docetaxel or TRAIL significantly enhance naive and docetaxel-resistant TNBC cell death via increased death receptor-mediated apoptosis and paraptosis, suggesting that targeting CIB1 may also overcome resistance to chemotherapeutics. Taken together, combination therapies that target CIB1 could prove to be a safe and durable strategy for treatment of TNBC and potentially other cancers. Citation Format: Alexander H. Chung, Tina M. Leisner, Gabrielle Dardis, Marissa Bivins, Leslie V. Parise. Potent treatment combinations with CIB1 depletion in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3967.