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Journal Articles Journal of Clinical Investigation Year : 2018

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

Sylvie Sauvaigo
  • Function : Author
Anne Lombès
  • Function : Author

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.
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hal-04513559 , version 1 (31-05-2024)

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Mehdi Touat, Tony Sourisseau, Nicolas Dorvault, Roman Chabanon, Marlène Garrido, et al.. DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade. Journal of Clinical Investigation, 2018, 128 (4), pp.1671-1687. ⟨10.1172/JCI90277⟩. ⟨hal-04513559⟩
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