PMID- 35459868 OWN - NLM STAT- MEDLINE DCOM- 20220426 LR - 20231213 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 13 IP - 1 DP - 2022 Apr 22 TI - A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. PG - 2206 LID - 10.1038/s41467-022-29905-1 [doi] LID - 2206 AB - Targeting ferroptosis, a unique cell death modality triggered by unrestricted lipid peroxidation, in cancer therapy is hindered by our incomplete understanding of ferroptosis mechanisms under specific cancer genetic contexts. KEAP1 (kelch-like ECH associated protein 1) is frequently mutated or inactivated in lung cancers, and KEAP1 mutant lung cancers are refractory to most therapies, including radiotherapy. In this study, we identify ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells. We further show that pharmacological inhibition of the CoQ-FSP1 axis sensitizes KEAP1 deficient lung cancer cells or patient-derived xenograft tumors to radiation through inducing ferroptosis. Together, our study identifies CoQ-FSP1 as a key downstream effector of KEAP1-NRF2 pathway and as a potential therapeutic target for treating KEAP1 mutant lung cancers. CI - (c) 2022. The Author(s). FAU - Koppula, Pranavi AU - Koppula P AUID- ORCID: 0000-0002-7567-1891 AD - Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. AD - The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. FAU - Lei, Guang AU - Lei G AUID- ORCID: 0000-0002-3282-0666 AD - Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. FAU - Zhang, Yilei AU - Zhang Y AUID- ORCID: 0000-0003-1407-0301 AD - Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. FAU - Yan, Yuelong AU - Yan Y AD - Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. FAU - Mao, Chao AU - Mao C AD - Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. FAU - Kondiparthi, Lavanya AU - Kondiparthi L AD - Kadmon Corporation, LLC, New York, NY, 10016, USA. FAU - Shi, Jiejun AU - Shi J AUID- ORCID: 0000-0001-9777-1183 AD - Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, 92697, USA. FAU - Liu, Xiaoguang AU - Liu X AUID- ORCID: 0000-0001-6977-5128 AD - Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. FAU - Horbath, Amber AU - Horbath A AUID- ORCID: 0000-0003-1482-8637 AD - Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. FAU - Das, Molina AU - Das M AD - Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. FAU - Li, Wei AU - Li W AUID- ORCID: 0000-0001-9931-5990 AD - Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, 92697, USA. FAU - Poyurovsky, Masha V AU - Poyurovsky MV AD - Kadmon Corporation, LLC, New York, NY, 10016, USA. FAU - Olszewski, Kellen AU - Olszewski K AD - Kadmon Corporation, LLC, New York, NY, 10016, USA. AD - The Barer Institute, Philadelphia, PA, 19104, USA. FAU - Gan, Boyi AU - Gan B AUID- ORCID: 0000-0001-8884-6040 AD - Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. bgan@mdanderson.org. AD - The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. bgan@mdanderson.org. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - R01 CA181196/CA/NCI NIH HHS/United States GR - R01 CA244144/CA/NCI NIH HHS/United States GR - R01 CA247992/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20220422 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (ferroptosis suppressor protein 1, human) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (KEAP1 protein, human) RN - 0 (Kelch-Like ECH-Associated Protein 1) RN - 0 (Mitochondrial Proteins) RN - 0 (NF-E2-Related Factor 2) RN - 1339-63-5 (Ubiquinone) SB - IM MH - *Apoptosis Regulatory Proteins/genetics/metabolism MH - *Ferroptosis/genetics MH - Humans MH - Kelch-Like ECH-Associated Protein 1/genetics/metabolism MH - Lipid Peroxidation MH - *Lung Neoplasms/genetics/radiotherapy MH - *Mitochondrial Proteins/genetics/metabolism MH - NF-E2-Related Factor 2/genetics/metabolism MH - *Ubiquinone/genetics/metabolism PMC - PMC9033817 COIS- K.O. is a full-time employee of the Barer Institute and a former full-time employee of Kadmon Corporation. L.K. and M.V.P. are full-time employees of Kadmon Corporation. EDAT- 2022/04/24 06:00 MHDA- 2022/04/27 06:00 PMCR- 2022/04/22 CRDT- 2022/04/23 05:22 PHST- 2021/09/27 00:00 [received] PHST- 2022/04/06 00:00 [accepted] PHST- 2022/04/23 05:22 [entrez] PHST- 2022/04/24 06:00 [pubmed] PHST- 2022/04/27 06:00 [medline] PHST- 2022/04/22 00:00 [pmc-release] AID - 10.1038/s41467-022-29905-1 [pii] AID - 29905 [pii] AID - 10.1038/s41467-022-29905-1 [doi] PST - epublish SO - Nat Commun. 2022 Apr 22;13(1):2206. doi: 10.1038/s41467-022-29905-1.