DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade
Mehdi Touat, … , Jean-Charles Soria, Sophie Postel-Vinay
Mehdi Touat, … , Jean-Charles Soria, Sophie Postel-Vinay
Published February 15, 2018
Citation Information: J Clin Invest. 2018;128(4):1671-1687. https://doi.org/10.1172/JCI90277.
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Research Article Oncology

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

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.

Authors

Mehdi Touat, Tony Sourisseau, Nicolas Dorvault, Roman M. Chabanon, Marlène Garrido, Daphné Morel, Dragomir B. Krastev, Ludovic Bigot, Julien Adam, Jessica R. Frankum, Sylvère Durand, Clement Pontoizeau, Sylvie Souquère, Mei-Shiue Kuo, Sylvie Sauvaigo, Faraz Mardakheh, Alain Sarasin, Ken A. Olaussen, Luc Friboulet, Frédéric Bouillaud, Gérard Pierron, Alan Ashworth, Anne Lombès, Christopher J. Lord, Jean-Charles Soria, Sophie Postel-Vinay

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Figure 6

ERCC1-deficient cells present a characteristic metabolic profile with alterations in the NAD+ biosynthesis pathway.

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ERCC1-deficient cells present a characteristic metabolic profile with al...
(A) Heatmap depicting relative abundance of 159 metabolites (annotation level 1, see Methods) determined by metabolomic profiling in the ERCC1-WT (n = 5 independent samples), ERCC1-Hez (n = 3), and ERCC1-KO (n = 3) cell lines from the A549 model. Samples (rows) and metabolites (columns) were reordered by hierarchical clustering using the Ward algorithm on their respective Euclidean distance matrices. (B) Box plots showing the relative abundance of central metabolites of the NAD+ pathway (NAD+, NADH, NADP, and nicotinamide) across the ERCC1-WT (n = 5 independent samples), ERCC1-Hez (n = 3), and ERCC1-KO (n = 3) cell lines with and without treatment by FK866. Data were centered on the ERCC1-WT vehicle group for comparative purposes. All statistical analyses and data representation were performed on preprocessed, log2-transformed and imputed data and reported as such without back transformation. Moderated statistics were used for differential analysis. Levels of significance were denoted as adjusted Benjamini-Hochberg P values to control the FDR.