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bioRxiv · 10.1101/2021.02.17.431266

Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries

Bazzaro, M.·Linder, S.·Shetty, M.·Zhang, X.·Clemente, V.
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Abstract

Ovarian 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.

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Bazzaro, M., Linder, S., Shetty, M., Zhang, X., Clemente, V.. 2021-02-17. Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries. https://doi.org/10.1101/2021.02.17.431266

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