HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma

Zou, Y.; Palte, M. J.; Deik, A. A.; Li, H.; Eaton, J. K.; Wang, W.; Tseng, Y.-Y.; Deasy, R.; Alimova, M.; Dancik, V.; Leshchiner, E. S.; Viswanathan, V. S.; Signoretti, S.; Choueiri, T. K.; Boehm, J. S.; Wagner, B. K.; Doench, J.; Clish, C. B.; Clemons, P. A.; Schreiber, S. L.

doi:10.1101/388041

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bioRxiv · 10.1101/388041

HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma

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Abstract

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-2-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-1{beta}-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.\n\nHIGHLIGHTSO_LIccRCC cells exhibit strong susceptibility to GPX4 inhibition-induced ferroptosis\nC_LIO_LIThe GPX4-dependent and ferroptosis-susceptible state in ccRCC is associated with PUFA-lipid abundance\nC_LIO_LIThe HIF-2-HILPDA axis promotes the selective deposition of PUFA-lipids and ferroptosis susceptibility\nC_LIO_LIAGPAT3 selectively synthesizes PUFA-phospholipids and primes renal cells for ferroptosis\nC_LI

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Zou, Y., Palte, M. J., Deik, A. A., Li, H., Eaton, J. K., Wang, W., Tseng, Y.-Y., Deasy, R., Alimova, M., Dancik, V., Leshchiner, E. S., Viswanathan, V. S., Signoretti, S., Choueiri, T. K., Boehm, J. S., Wagner, B. K., Doench, J., Clish, C. B., Clemons, P. A., Schreiber, S. L.. 2018-08-09. HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma. https://doi.org/10.1101/388041

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