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

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…

• DC
  Dana-Farber/Harvard Cancer Center

  Award: CA101942
• NI
  National Institutes of Health

  Awards: P50 CA101942-13, P50 CA101942, T32HL007627
• NH
  National Heart, Lung, and Blood Institute

  Award: T32HL007627
• NC
  National Cancer Institute

  Awards: U01CA217848, CA101942, P50 CA101942