Abstract A019: Inhibition of nicotinamide adenine dinucleotide (NAD) production is a potent therapeutic strategy to inactivate homologous recombination in cancer cells

• DOI: 10.1158/1538-8514.synthleth24-a019
• Publication Date: 2024-06-10T07:06:23Z
• Authors: Sadaf Valeh Sheida; Thibaut Peterlini; Mélissa Thomas; Guy Poirier; Jean-Yves Masson
• Keywords: Synthetic Lethality; Olaparib; PALB2; PARP inhibitor; Nicotinamide phosphoribosyltransferase

Abstract Homologous recombination (HR) is the most faithful DNA double-strand breaks (DSBs) repairing pathway. HR deficiency (HRD) can result from mutations in BRCA1, BRCA2, and PALB2, which are associated with genomic instability cancer. deficient cells survive through use of alternative repair pathways. Therefore, inhibiting these pathways HRD trigger cancer cell death. This phenomenon called synthetic lethality. The best-known example lethality that involving BRCA1/BRCA2/PALB2 PARP-1 inhibition by Olaparib. However, ∼40% patients will develop resistance to PARP because several mechanisms, including a second mutation BRCA1/2, restoring their full-length expression or RAD51 overexpression. one important mediators as it promotes invasion sister chromatid allowing DSB repair. There many pieces evidence show overexpression correlated worse overall survival. Our hypothesis targeting deficiency, particularly resistant standard treatments. We thus sought find inhibitors recombinase. have developed an cellulo screening technique test direct effect chemical compounds on foci formation following irradiation. Using this technique, we identified , among 1381 molecules, FK866 (Daporinad) Nicotinamide Phosphoribosyltransferase Inhibitor (NAMPTi). NAMPT involved producing cellular Adenine Dinucleotide (NAD+), plays crucial role various metabolic processes within cell, primarily energy production Remarkably, treatment Daporinad reduced triggered destabilization protein proteasome. seemed be specific for RAD51, NHEJ factors were not affected NAMPTi. present data related our objectives: i) Monitoring different lines originated types has shown survival Western blot qPCR techniques used investigate mRNA level using Zeiss Celldiscoverer 7 system Incucyte live imaging microscopy observe survival; ii) To confirm Daporinad, monitor other reporter systems; iii) In long term, aim evaluate vivo tumor growth pre-clinical models, such mouse xenografts. conclusion, small molecules affecting provide source new therapies Citation Format: Sadaf Valeh Sheida, Thibaut Peterlini, Mélissa Thomas, Guy Poirier, Jean-Yves Masson. Inhibition nicotinamide adenine dinucleotide (NAD) potent therapeutic strategy inactivate homologous [abstract]. In: Proceedings AACR Special Conference Cancer Research: Expanding Translating Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Ther 2024;23(6 Suppl):Abstract nr A019.