Fumarate hydratase inactivation in hereditary leiomyomatosis and renal cell cancer is synthetic lethal with ferroptosis induction

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome characterized by inactivation of the Krebs cycle enzyme fumarate hydratase (FH). HLRCC patients are at high risk of developing kidney cancer of type 2 papillary morphology that is refractory to current radiotherapy, immunotherapy and chemotherapy. Hence, an effective therapy for this deadly form of cancer is urgently needed. Here, we show that FH inactivation (FH−/−) proves synthetic lethal with inducers of ferroptosis, an iron‐dependent and nonapoptotic form of cell death. Specifically, we identified gene signatures for compound sensitivities based on drug responses for 9 different drug classes against the NCI‐60 cell lines. These signatures predicted that ferroptosis inducers would be selectively toxic to FH−/− cell line UOK262. Preferential cell death against UOK262‐FH−/− was confirmed with 4 different ferroptosis inducers. Mechanistically, the FH−/− sensitivity to ferroptosis is attributed to dysfunctional GPX4, the primary cellular defender against ferroptosis. We identified that C93 of GPX4 is readily post‐translationally modified by fumarates that accumulate in conditions of FH−/−, and that C93 modification represses GPX4 activity. Induction of ferroptosis in FH‐inactivated tumors represents an opportunity for synthetic lethality in cancer. FH inactivation is associated with deadly renal cell carcinomas that are refractory to current treatments. We demonstrate that FH‐inactivated tumors are preferentially susceptible to ferroptosis.