Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries

Abstract

SummaryOvarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A a member of the SWI/SNF chromatin remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells, however the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here we show that ARID1A-loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated to increase of C-myc and to increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide the for targeting mitochondrial activity in ARID1A-mutanted OCCCs.