Show simple item record

dc.contributor.authorTouat, Men_US
dc.contributor.authorSourisseau, Ten_US
dc.contributor.authorDorvault, Nen_US
dc.contributor.authorChabanon, RMen_US
dc.contributor.authorGarrido, Men_US
dc.contributor.authorMorel, Den_US
dc.contributor.authorKrastev, DBen_US
dc.contributor.authorBigot, Len_US
dc.contributor.authorAdam, Jen_US
dc.contributor.authorFrankum, JRen_US
dc.contributor.authorDurand, Sen_US
dc.contributor.authorPontoizeau, Cen_US
dc.contributor.authorSouquère, Sen_US
dc.contributor.authorKuo, M-Sen_US
dc.contributor.authorSauvaigo, Sen_US
dc.contributor.authorMardakheh, Fen_US
dc.contributor.authorSarasin, Aen_US
dc.contributor.authorOlaussen, KAen_US
dc.contributor.authorFriboulet, Len_US
dc.contributor.authorBouillaud, Fen_US
dc.contributor.authorPierron, Gen_US
dc.contributor.authorAshworth, Aen_US
dc.contributor.authorLombès, Aen_US
dc.contributor.authorLord, CJen_US
dc.contributor.authorSoria, J-Cen_US
dc.contributor.authorPostel-Vinay, Sen_US
dc.date.accessioned2018-09-26T08:35:46Z
dc.date.issued2018-04en_US
dc.identifier.citationThe Journal of clinical investigation, 2018, 128 (4), pp. 1671 - 1687en_US
dc.identifier.issn0021-9738en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2869
dc.identifier.eissn1558-8238en_US
dc.identifier.doi10.1172/jci90277en_US
dc.description.abstractSynthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. Excision repair cross-complementation group 1 (ERCC1) deficiency is frequently found in non-small-cell lung cancer (NSCLC), making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in the disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house-generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). We also found reduced NAMPT expression in NSCLC samples with low levels of ERCC1. These metabolic alterations were a primary effect of ERCC1 deficiency, and caused selective exquisite sensitivity to small-molecule NAMPT inhibitors, both in vitro - ERCC1-deficient cells being approximately 1,000 times more sensitive than ERCC1-WT cells - and in vivo. Using transmission electronic microscopy and functional metabolic studies, we found that ERCC1-deficient cells harbor mitochondrial defects. We propose a model where NAD+ acts as a regulator of ERCC1-deficient NSCLC cell fitness. These findings open therapeutic opportunities that exploit a yet-undescribed nuclear-mitochondrial synthetic lethal relationship in NSCLC models, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy.en_US
dc.formatPrint-Electronicen_US
dc.format.extent1671 - 1687en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_US
dc.subjectAnimalsen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectMice, Nudeen_US
dc.subjectCarcinoma, Non-Small-Cell Lungen_US
dc.subjectLung Neoplasmsen_US
dc.subjectNeoplasms, Experimentalen_US
dc.subjectNADen_US
dc.subjectEndonucleasesen_US
dc.subjectDNA-Binding Proteinsen_US
dc.subjectNeoplasm Proteinsen_US
dc.subjectCytokinesen_US
dc.subjectDNA Repairen_US
dc.subjectNicotinamide Phosphoribosyltransferaseen_US
dc.subjectA549 Cellsen_US
dc.titleDNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-02-01en_US
rioxxterms.versionofrecord10.1172/jci90277en_US
rioxxterms.licenseref.startdate2018-04en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfThe Journal of clinical investigationen_US
pubs.issue4en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublisheden_US
pubs.volume128en_US
pubs.embargo.termsNot knownen_US
icr.researchteamGene Functionen_US
dc.contributor.icrauthorLord, Christopheren_US
dc.contributor.icrauthorKrastev, Dragomiren_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record