A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis

Yilong Zou, Michael J. Palte, Amy A. Deik, Haoxin Li, John K. Eaton, Wenyu Wang, Yuen-Yi Tseng, Rebecca Deasy, Maria Kost-Alimova, Vlado Dančík, Elizaveta S. Leshchiner, Vasanthi S. Viswanathan, Sabina Signoretti, Toni K. Choueiri, Jesse S. Boehm, Bridget K. Wagner, John G. Doench, Clary B. Clish, Paul A. Clemons and Stuart L. Schreiber ()
Additional contact information
Yilong Zou: The Broad Institute
Michael J. Palte: The Broad Institute
Amy A. Deik: The Broad Institute
Haoxin Li: The Broad Institute
John K. Eaton: The Broad Institute
Wenyu Wang: The Broad Institute
Yuen-Yi Tseng: The Broad Institute
Rebecca Deasy: The Broad Institute
Maria Kost-Alimova: The Broad Institute
Vlado Dančík: The Broad Institute
Elizaveta S. Leshchiner: The Broad Institute
Vasanthi S. Viswanathan: The Broad Institute
Sabina Signoretti: Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School
Toni K. Choueiri: Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School
Jesse S. Boehm: The Broad Institute
Bridget K. Wagner: The Broad Institute
John G. Doench: The Broad Institute
Clary B. Clish: The Broad Institute
Paul A. Clemons: The Broad Institute
Stuart L. Schreiber: The Broad Institute

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4) with small-molecules. Using CRISPR screening and lipidomic profiling, we identify the hypoxia-inducible factor (HIF) pathway as a driver of this vulnerability. In renal CCCs, HIF-2α selectively enriches polyunsaturated lipids, the rate-limiting substrates for lipid peroxidation, by activating the expression of hypoxia-inducible, lipid droplet-associated protein (HILPDA). Our study suggests targeting GPX4 as a therapeutic opportunity in CCCs, and highlights that therapeutic approaches can be identified on the basis of cell states manifested by morphological and metabolic features in hard-to-treat cancers.

Date: 2019
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DOI: 10.1038/s41467-019-09277-9

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