HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma
Michael J Palte,
Amy A Deik,
John K. Eaton,
Elizaveta S Leshchiner,
Vasanthi S. Viswanathan,
Toni K. Choueiri,
Jesse S. Boehm,
Bridget K. Wagner,
Clary B. Clish,
Paul A Clemons,
Stuart L Schreiber
Posted 09 Aug 2018
bioRxiv DOI: 10.1101/388041
Posted 09 Aug 2018
Kidney cancers are characterized by extensive metabolic reprogramming and resistance to a broad range of anti-cancer therapies. By interrogating the Cancer Therapeutics Response Portal compound sensitivity dataset, we show that cells of clear-cell renal cell carcinoma (ccRCC) possess a lineage-specific vulnerability to ferroptosis that can be exploited by inhibiting glutathione peroxidase 4 (GPX4). Using genome-wide CRISPR screening and lipidomic profiling, we reveal that this vulnerability is driven by the HIF-2α - HILPDA pathway by inducing a polyunsaturated fatty acyl (PUFA)-lipid-enriched cell state that is dependent on GPX4 for survival and susceptible to ferroptosis. This cell state is developmentally primed by the HNF-1β - 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) axis in the renal lineage. In addition to PUFA metabolism, ferroptosis is facilitated by a phospholipid flippase TMEM30A involved in membrane topology. Our study uncovers an oncogenesis-associated vulnerability, delineates the underlying mechanisms and suggests targeting GPX4 to induce ferroptosis as a therapeutic opportunity in ccRCC.
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