Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 4, Pages 1671-1687Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI90277
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Funding
- ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Sante, National Alliance for Life Sciences Health)
- Etablissement Public Chancellerie des Universites de Paris (Legs Poix)
- Fondation de France [Engt 2013 00038309]
- Fondation ARC pour la Recherche sur le Cancer [PJA 20131200170]
- Agence National de la Recherche [ANR-10-IHBU-0001]
- SIRIC SOCRATE - Institut National du Cancer [INCa-DGOS-INSERM6043]
- Cancer Research UK [C347/A8363]
- Breast Cancer Now
- EU FP7 project EurocanPlatform [260791]
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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.
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