Advertisement

 

 

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

DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade.
Author Information (click to view)

Touat M, Sourisseau T, Dorvault N, Chabanon RM, Garrido M, Morel D, Krastev DB, Bigot L, Adam J, Frankum J, Durand S, Pontoizeau C, Souquère S, Kuo MS, Sauvaigo S, Mardakheh F, Sarasin A, Olaussen KA, Friboulet L, Bouillaud F, Pierron G, Ashworth A, Lombès A, Lord CJ, Soria JC, Postel-Vinay S,


Touat M, Sourisseau T, Dorvault N, Chabanon RM, Garrido M, Morel D, Krastev DB, Bigot L, Adam J, Frankum J, Durand S, Pontoizeau C, Souquère S, Kuo MS, Sauvaigo S, Mardakheh F, Sarasin A, Olaussen KA, Friboulet L, Bouillaud F, Pierron G, Ashworth A, Lombès A, Lord CJ, Soria JC, Postel-Vinay S, (click to view)

Touat M, Sourisseau T, Dorvault N, Chabanon RM, Garrido M, Morel D, Krastev DB, Bigot L, Adam J, Frankum J, Durand S, Pontoizeau C, Souquère S, Kuo MS, Sauvaigo S, Mardakheh F, Sarasin A, Olaussen KA, Friboulet L, Bouillaud F, Pierron G, Ashworth A, Lombès A, Lord CJ, Soria JC, Postel-Vinay S,

Advertisement

The Journal of clinical investigation 2018 02 15() doi 10.1172/JCI90277

Abstract

Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. ERCC1 deficiency is frequently found in non-small cell lung cancers, making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in this 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 further evidenced 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 1000 times more sensitive – 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 fitness. These findings open therapeutic opportunities that exploit a yet undescribed nuclear – mitochondrial synthetic lethal relationship in cancer cells, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy.

Submit a Comment

Your email address will not be published. Required fields are marked *

seventeen + 10 =

[ HIDE/SHOW ]