DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade
| Autor: | Julien Adam, Anne Lombès, Sophie Postel-Vinay, Frédéric Bouillaud, Daphné Morel, Sylvère Durand, Mei-Shiue Kuo, Marlène Garrido, Faraz K. Mardakheh, Mehdi Touat, Clément Pontoizeau, Christopher J. Lord, Tony Sourisseau, Jean-Charles Soria, Ludovic Bigot, Jessica Frankum, Alan Ashworth, Gérard Pierron, Dragomir B. Krastev, Nicolas Dorvault, Roman M. Chabanon, Alain Sarasin, Luc Friboulet, Ken A. Olaussen, Sylvie Souquere, Sylvie Sauvaigo |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Lung Neoplasms DNA Repair DNA repair Nicotinamide phosphoribosyltransferase Mice Nude Synthetic lethality Mitochondrion Mice 03 medical and health sciences chemistry.chemical_compound Carcinoma Non-Small-Cell Lung DNA Repair Protein Animals Humans Nicotinamide Phosphoribosyltransferase Neoplasms Experimental General Medicine Endonucleases NAD Neoplasm Proteins DNA-Binding Proteins 030104 developmental biology chemistry A549 Cells Cancer research Cytokines NAD+ kinase ERCC1 Research Article Nucleotide excision repair |
| Zdroj: | Journal of Clinical Investigation. 128:1671-1687 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci90277 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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