Glycogen phosphorylase inhibition alongside taxol chemotherapy synergistically elicits ferroptotic cell death in clear cell ovarian and kidney cancers

Background Clear cell carcinomas (CCCs) are a distinct histopathological subtype defined by a clear cytoplasm comprised of glycogen and lipids and characterised by poor prognosis and widespread chemoresistance. In the present work we investigate glycogen metabolism as a targetable modality for these cancers. Methods and Results Adopting the indole carboxamide site pan-glycogen phosphorylase inhibitor CP91149 against clear cell ovarian and renal cancer cell line models, we note antiproliferative and antimigratory effects, as well as energetic stress reflected by reduced ATP pools and increased superoxide-derived reactive oxygen species. Following this, using the agent alongside standard of care chemotherapies for clear cell ovarian (ccOC) and renal cell carcinoma (ccRCC), we note specific synergy with microtubule disrupting chemotherapy paclitaxel, a phenomenon retained in ccOC lines made stably resistant to paclitaxel. Rescue experiments, as well as phenotypic assays suggest that combination-treated cells undergo ferroptotic cell death. We postulate this synergistic efficacy to arise from subjecting the already hypersensitive clear cell cancers to the mitochondrial stress elicited by taxol chemotherapy alongside the oxidative stress augured by glycogen phosphorylase inhibition. Conclusions Given that CCCs are widely chemoresistant, the present work potentially presents a novel therapeutic avenue for this shared histotype. ### Competing Interest Statement The authors have declared no competing interest. * CCC : Clear cell carcinoma ccOC : Clear cell ovarian cancer ccRCC : Clear cell renal cell carcinoma GPX4 : glutathione peroxidase GS : glycogen synthase PYG : Glycogen Phosphorylase CI : Combination Index HGSOC : High Grade Serous Ovarian Cancer PacR : Paclitaxel Resistant