{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:24:24Z","timestamp":1791822264530,"version":"4.3.4"},"reference-count":36,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2018,7,20]],"date-time":"2018-07-20T00:00:00Z","timestamp":1532044800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2018,7,20]],"date-time":"2018-07-20T00:00:00Z","timestamp":1532044800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DGE\u20101143953"],"award-info":[{"award-number":["DGE\u20101143953"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R21ES027920"],"award-info":[{"award-number":["R21ES027920"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:p>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 <jats:italic>FH<\/jats:italic> inactivation (<jats:italic>FH<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) proves synthetic lethal with inducers of ferroptosis, an iron\u2010dependent 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\u201060 cell lines. These signatures predicted that ferroptosis inducers would be selectively toxic to <jats:italic>FH<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> cell line UOK262. Preferential cell death against UOK262\u2010<jats:italic>FH<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> was confirmed with 4 different ferroptosis inducers. Mechanistically, the <jats:italic>FH<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> sensitivity to ferroptosis is attributed to dysfunctional GPX4, the primary cellular defender against ferroptosis. We identified that C93 of GPX4 is readily post\u2010translationally modified by fumarates that accumulate in conditions of <jats:italic>FH<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>, and that C93 modification represses GPX4 activity. Induction of ferroptosis in <jats:italic>FH<\/jats:italic>\u2010inactivated tumors represents an opportunity for synthetic lethality in cancer.<\/jats:p>","DOI":"10.1111\/cas.13701","type":"journal-article","created":{"date-parts":[[2018,6,19]],"date-time":"2018-06-19T15:08:19Z","timestamp":1529420899000},"page":"2757-2766","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":99,"title":["Fumarate hydratase inactivation in hereditary leiomyomatosis and renal cell cancer is synthetic lethal with ferroptosis induction"],"prefix":"10.1111","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3095-4641","authenticated-orcid":false,"given":"Michael J.","family":"Kerins","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology College of Pharmacy University of Arizona Tucson AZ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Milligan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology College of Pharmacy University of Arizona Tucson AZ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Wohlschlegel","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry David Geffen School of Medicine University of California Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikseng","family":"Ooi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology College of Pharmacy University of Arizona Tucson AZ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,7,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng849"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10689-014-9735-2"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi227"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.08.024"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.02.013"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00079-17"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.09.006"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.143"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2951"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0146021"},{"key":"e_1_2_7_12_1","unstructured":"TeamRC.R: A language and environment for statistical computing. 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