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J Clin Invest. 2018 Apr 2;128(4):1671-1687. doi: 10.1172/JCI90277. Epub 2018 Mar 19.

DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade.

Author information

1
Inserm U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
2
Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Université Paris-Saclay, Villejuif, France.
3
Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMRS1127, Institut du Cerveau et de la Moelle Epiniere, ICM, Paris, France.
4
Inserm U981, ATIP-Avenir Team, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
5
The CRUK Gene Function Laboratory and Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom.
6
Département de Biologie et Pathologies Médicales, and.
7
Metabolomics Platform, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
8
Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
9
Service de Biochimie Métabolomique et Protéomique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
10
Inserm U1163, Institut Imagine, Equipe "Génétique des Maladies Mitochondriales" and Paris Descartes University, Paris, France.
11
CNRS UMR-9196, Functional Organization of the Cell, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
12
LXRepair, Grenoble, France.
13
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
14
CNRS UMR-8200, Laboratory of Genetic Stability and Oncogenesis, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
15
Faculté de médecine Paris-Sud XI, Kremlin-Bicêtre.
16
Inserm U1016, CNRS UMR 8104, Institut Cochin, Université Paris-Descartes-Paris 5, Paris, France.
17
UCSF Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, USA.

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.

KEYWORDS:

DNA repair; Lung cancer; Mitochondria; Oncology

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