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keap, cells, ferroptosis, cancer, fsp, pubmed, cell, fig, article, lung, google, scholar, cas, data, nrf, supplementary, central, lipid, tumor, levels, gpx, expression, peroxidation, mutant, nature, coq, cba, cancers, deficient, rsl, treatment, death, tumors, study, deletion, target, xray, slca, fin, resistance, survival, deficiency, irradiation, analysis, protein, fins, source, radiation, class, pathway,

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nature portfolio privacy policy middle line represents advertising references jiang apoptosis inhibitor z-vad-fmk peer review fsp1 promoter-luciferase activities depmap data portal p62-keap1-nrf2 pathway protects tissue sections reprints foxo-bnip3 axis exerts perform real-time pcr cancer genome atlas japan hek-293t cells treated cancer research communities author correspondence original author cystine transporter slc7a11/xct keap1 deficiency-induced resistance n-terminal v5 tag thermofisher scientific esmo open 5 kopchick research award peer reviewer reports rt-induced lipid peroxidation slc7a11-keap1 dko cells rt-induced cell death21 cell culture media institutional review board lentivirus vector plx304-blasticidin necroptosis inhibitor necrostatin-1s gpx4-keap1 dko cells org/portal/ p53-inducible gene downregulated bi-dimensional tumor measurements remove serum-derived coq institutional research fund 100 mm tris-hcl ph8 cold dmem media 100 μm tert-butyl-hydroquinone molina das & boyi gan tsc-mtor signaling pathways lncrna nbr2 engages data availability glutathione-independent ferroptosis suppressor detailed information patient-derived xenograft tumors

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• Unsolved mysteries: how does lipid peroxidation cause ferroptosis?

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         headline:A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers
         description: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. KEAP1 mutations are frequently observed in NSCLC and lead to drug resistance. Here, the authors show that KEAP1 mutations in lung cancer cells leads to FSP1 upregulation through NRF2, resulting in ferroptosis resistance and radioresistance.
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      description: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. KEAP1 mutations are frequently observed in NSCLC and lead to drug resistance. Here, the authors show that KEAP1 mutations in lung cancer cells leads to FSP1 upregulation through NRF2, resulting in ferroptosis resistance and radioresistance.
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            name:Kadmon Corporation, LLC
            address:
               name:Kadmon Corporation, LLC, New York, USA
               type:PostalAddress
            type:Organization
      name:Jiejun Shi
      url:http://orcid.org/0000-0001-9777-1183
      affiliation:
            name:University of California
            address:
               name:Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, USA
               type:PostalAddress
            type:Organization
      name:Xiaoguang Liu
      url:http://orcid.org/0000-0001-6977-5128
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Amber Horbath
      url:http://orcid.org/0000-0003-1482-8637
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Molina Das
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
      name:Wei Li
      url:http://orcid.org/0000-0001-9931-5990
      affiliation:
            name:University of California
            address:
               name:Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, USA
               type:PostalAddress
            type:Organization
      name:Masha V. Poyurovsky
      affiliation:
            name:Kadmon Corporation, LLC
            address:
               name:Kadmon Corporation, LLC, New York, USA
               type:PostalAddress
            type:Organization
      name:Kellen Olszewski
      affiliation:
            name:Kadmon Corporation, LLC
            address:
               name:Kadmon Corporation, LLC, New York, USA
               type:PostalAddress
            type:Organization
            name:The Barer Institute
            address:
               name:The Barer Institute, Philadelphia, USA
               type:PostalAddress
            type:Organization
      name:Boyi Gan
      url:http://orcid.org/0000-0001-8884-6040
      affiliation:
            name:The University of Texas MD Anderson Cancer Center
            address:
               name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
               type:PostalAddress
            type:Organization
            name:The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences
            address:
               name:The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, USA
      name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Kadmon Corporation, LLC, New York, USA
      name:Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, USA
      name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, USA
      name:Kadmon Corporation, LLC, New York, USA
      name:Kadmon Corporation, LLC, New York, USA
      name:The Barer Institute, Philadelphia, USA
      name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
      name:The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, USA

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