Abstract 3211: Inhibition of autophagy potentiates cytotoxicity of CX-5461 treatment in chemoresistant epithelial ovarian cancer

Abstract

Abstract Epithelial ovarian cancer remains a deadly diagnosis with poor prognosis and patients succumbing to chemoresistant disease in 80% of cases. Mechanisms of chemoresistance are numerous, but we have identified ribosomal biogenesis basal machinery as being a common upregulated signaling network in response to chemotherapeutic insult. Tumors treated with chemotherapy showed dramatic increases in size and morphology of nucleoli, suggesting global changes in ribosomal synthesis with stress. We next sought to use the RNA Polymerase I inhibitor CX-5461 to identify biologic changes in targeting ribosomal machinery that may allow resensitization to chemotherapy. CX-5461 induced autophagy, senescence and mitotic catastrophe in ovarian cancer cell lines Overall, 13 ovarian cancer lines examined were highly sensitive to Pol I inhibition by MTT, with IC50s ranging from 25nM to 2μM, and chemoresistant lines were generally more sensitive to CX-5461. In p53 mutant cells CX-5461 appears to be primarily cytostatic with mitotic catastrophe being a relatively rare event accompanying cytokinesis failure. This could be indicative of the cells successfully using autophagy to decrease ribosome requirements and evade treatment. When treated in combination with chloroquine as an autophagy inhibitor IC50s decreased to 550nM in HeyA8 (from 2μM), 70nM for HeyA8MDR (from 191nM), 110nM in SKOV3 (from 595nM) and 60nM for SKOV3TR-ip2 (from 109nM) with abundant multinucleated cells, suggesting synergy between ribosomal synthesis and autophagy inhibitors in vitro. Chloroquine administration appears to push cell to mitotic catastrophe after co-administration with CX-5461, thereby enhancing cytotoxicity over cytostatic endpoints after treatment, even in multi-drug resistant cell populations. Inhibition of autophagy appears to enhance efficacy of RNA Polymerase I inhibition in both sensitive and chemoresistant populations, prompting a potential new approach to chemoresistant disease. Citation Format: Robert Cornelison, Danielle C. Llaneza, Yulia Petrova, Zachary C. Dobbin, David A. Schneider, Charles N. Landen. Inhibition of autophagy potentiates cytotoxicity of CX-5461 treatment in chemoresistant epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3211. doi:10.1158/1538-7445.AM2017-3211