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

Abstract

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.

Signaling pathway network alterations in human ovarian cancers identified with quantitative mitochondrial proteomics

“…For example, by microarray analysis, one confirmed that fumarate hydratase messenger RNA (TCA cycle II pathway) was low expression in renal cancer cells. Consistence with the possibility that altered gene expression of fumarate hydratase represented one change to a more anaerobic state [ 40 ]. Overnutrition was known as a confirmed independent cancer risk factor.…”

Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy

“…About ten years later, the same group showed that erastin blocks the x c − system and inhibits GSH synthesis, in one of the first examples of synthetic lethality connected to GSH metabolism [46]. Erastin efficiently kills also hereditary leiomyomatosis and renal cell cancer cells characterized by inactivation of the enzyme fumarate hydratase (FH), through induction of ferroptosis [74]. The acquisition of mutations driving oncogenic transformation confers an advantage to tumour cells but can also bring along collateral effects that expose vulnerabilities.…”

Clinical characteristics and treatments of hereditary leiomyomatosis renal cell carcinoma: two case reports and literature review

“…Multiple types of mutations in FH gene are relevant to HLRCC, such as missense, frameshift, nonsense and so on, all types can cause the accumulation of fumarate, which increases the risk of developing type 2 PRCC [7]. The mechanism is unclear, Michael J et al reported that FH inactivation may result in accumulation of ferroptosis in tumors, cause an iron-dependent and no apoptotic form of cell death, which represents an opportunity for synthetic in cancer [8]. El-hariry I et al prove that mutation of the FH gene causes cell hypoxia, leads to cellular metabolic derangement and activates hypoxia-inducible factor(HIF)pathway, accelerating the release of many kinds of tumor-promoting factors, like VEGF,TGF-α,PDGF and mTOR pathway [9].…”