DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade.
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Date
2018-04-02Author
Touat, M
Sourisseau, T
Dorvault, N
Chabanon, RM
Garrido, M
Morel, D
Krastev, DB
Bigot, L
Adam, J
Frankum, JR
Durand, S
Pontoizeau, C
Souquère, S
Kuo, M-S
Sauvaigo, S
Mardakheh, F
Sarasin, A
Olaussen, KA
Friboulet, L
Bouillaud, F
Pierron, G
Ashworth, A
Lombès, A
Lord, CJ
Soria, J-C
Postel-Vinay, S
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Humans
Mice
Mice, Nude
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Neoplasms, Experimental
NAD
Endonucleases
DNA-Binding Proteins
Neoplasm Proteins
Cytokines
DNA Repair
Nicotinamide Phosphoribosyltransferase
A549 Cells
Research team
Gene Function
Language
eng
Date accepted
2018-02-01
License start date
2018-04
Citation
The Journal of clinical investigation, 2018, 128 (4), pp. 1671 - 1687
Publisher
AMER SOC CLINICAL INVESTIGATION INC