dc.contributor.author | Touat, M | |
dc.contributor.author | Sourisseau, T | |
dc.contributor.author | Dorvault, N | |
dc.contributor.author | Chabanon, RM | |
dc.contributor.author | Garrido, M | |
dc.contributor.author | Morel, D | |
dc.contributor.author | Krastev, DB | |
dc.contributor.author | Bigot, L | |
dc.contributor.author | Adam, J | |
dc.contributor.author | Frankum, JR | |
dc.contributor.author | Durand, S | |
dc.contributor.author | Pontoizeau, C | |
dc.contributor.author | Souquère, S | |
dc.contributor.author | Kuo, M-S | |
dc.contributor.author | Sauvaigo, S | |
dc.contributor.author | Mardakheh, F | |
dc.contributor.author | Sarasin, A | |
dc.contributor.author | Olaussen, KA | |
dc.contributor.author | Friboulet, L | |
dc.contributor.author | Bouillaud, F | |
dc.contributor.author | Pierron, G | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Lombès, A | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Soria, J-C | |
dc.contributor.author | Postel-Vinay, S | |
dc.date.accessioned | 2018-09-26T08:35:46Z | |
dc.date.issued | 2018-04-02 | |
dc.identifier.citation | The Journal of clinical investigation, 2018, 128 (4), pp. 1671 - 1687 | |
dc.identifier.issn | 0021-9738 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/2869 | |
dc.identifier.eissn | 1558-8238 | |
dc.identifier.doi | 10.1172/jci90277 | |
dc.description.abstract | Synthetic 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 1671 - 1687 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER SOC CLINICAL INVESTIGATION INC | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, Nude | |
dc.subject | Carcinoma, Non-Small-Cell Lung | |
dc.subject | Lung Neoplasms | |
dc.subject | Neoplasms, Experimental | |
dc.subject | NAD | |
dc.subject | Endonucleases | |
dc.subject | DNA-Binding Proteins | |
dc.subject | Neoplasm Proteins | |
dc.subject | Cytokines | |
dc.subject | DNA Repair | |
dc.subject | Nicotinamide Phosphoribosyltransferase | |
dc.subject | A549 Cells | |
dc.title | DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-02-01 | |
rioxxterms.versionofrecord | 10.1172/jci90277 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2018-04 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | The Journal of clinical investigation | |
pubs.issue | 4 | |
pubs.notes | Not known | |
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.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-status | Published | |
pubs.volume | 128 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Krastev, Dragomir | |
dc.contributor.icrauthor | Lord, Christopher | |