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

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

Journal article

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

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Touat, M., Sourisseau, T., Dorvault, N., Chabanon, R. M., Garrido, M., Morel, D., Krastev, D. B., Bigot, L., Adam, J., Frankum, J. R., Durand, S., Pontoizeau, C., Souquère, S., Kuo, M.-S., Sauvaigo, S., Mardakheh, F., Sarasin, A., Olaussen, K. A., Friboulet, L., … Postel-Vinay, S. (2018). DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade. The Journal of Clinical Investigation, 128(4), 1671–1687.

MLA Style

Touat, M, et al. “DNA Repair Deficiency Sensitizes Lung Cancer Cells to NAD+ Biosynthesis Blockade.” The Journal of Clinical Investigation, vol. 128, no. 4, 2018, pp. 1671–87.

Chicago Style

Touat, M, T Sourisseau, N Dorvault, et al. 2018. “DNA Repair Deficiency Sensitizes Lung Cancer Cells to NAD+ Biosynthesis Blockade.” The Journal of Clinical Investigation 128 (4): 1671–87.
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