Characterize the metabolic landscape of ARID1A-mutated ovarian cancer

Abstract Ovarian clear cell carcinoma (OCCC) is a rare and highly lethal gynecological cancer. The majority of OCCC patients carry inactivating mutations in ARID1A, a component of the SWI/SNF chromatin- remodeling complex, leading to a lack of response to standard chemotherapy and poor prognosis. To address this unmet medical need, recent research, including from our own laboratory, has suggested that targeting mitochondrial respiration may be a promising approach for treating ARID1A-mutated tumors. However, there is still a significant knowledge gap in understanding the specific mitochondrial Electron Transport Chain (mETC) components that contribute to the dependency of ARID1A-deficient cancer cells on mitochondrial respiration. Current mitochondrial inhibitors lack specificity and often cause severe side effects. This grant proposal aims to identify unique proteomic and functional mitochondrial signatures associated with ARID1A deficiency in OCCC tumors. Additionally, it seeks to perform a genetic screen of mETC drop-out in ARID1A-proficient and deficient cells. The results from this research could reveal potential therapeutic vulnerabilities within the mETC for ARID1A- deficient tumors, not only in OCCC but also in other cancers with ARID1A mutations. The innovative aspect of this grant lies in conducting a comprehensive analysis of mETC in ARID1A wild-type and mutated tumors and performing the first-ever mETC genetic screen in ARID1A-proficient and deficient cells. The findings from this research have the potential to uncover novel therapeutic targets for ARID1A-deficient OCCC tumors and may have broader implications for unresponsive tumors in different contexts.