The application of an innate immune agonist in the treatment of ovarian cancer

Current ovarian cancer drug regimens, including taxanes and platinum‐based agents, are susceptible to chemoresistance necessitating development of novel therapies. Within tumors, pathogen‐derived ligands, such as double stranded RNA (dsRNA), can activate receptors capable of inducing apoptosis. We have found in ovarian cancer cell lines that dsRNA treatment alters cell survival. Our objective is to determine the mechanism of dsRNA‐induced apoptosis. Two sample categories, responders and non‐responders, were identified upon dsRNA treatment. Responders show a dsRNA‐induced increase in dsRNA receptor expression whereas non‐responders do not. When dsRNA receptors are overexpressed in non‐responders, dsRNA‐induced cell death increases. In responders, NF‐kappaB, IFN‐beta and caspase 3 activation occur. Cell death is caspase‐ and IFN‐dependent. In non‐responders, basal level autophagy was found and increased with dsRNA stimulation, but no increase in cell death was observed. Autophagy may contribute to the non‐responsive phenotype. When treated with a combination of dsRNA + HDAC inhibitor, cell death was enhanced through an, as yet, undefined mechanism that may find application in chemoresistant ovarian cancers. Funding by NIH‐NCI.