Abstract 3086: NAPRT silencing in oncometabolite-producing cancers confers therapeutic vulnerabilities to NAD+ depletion

Abstract

Abstract Cancer associated mutations in citric acid cycle enzymes cause overproduction of 2-hydroxyglutarate (2HG), fumarate, or succinate, commonly referred to as oncometabolites. These oncometabolite-producing mutations are prevalent in 70% of gliomas, >76% of hereditary leiomyomatosis and renal cell carcinoma, and >25% of paraganglioma and pheochromocytomas, respectively and contribute to their progression. These oncometabolite-producing cancers harbor vulnerabilities in multiple cellular pathways because of their competitive inhibition of alpha ketoglutarate dependent dioxygenases, which includes the ten eleven translocation (TET) enzymes. As a result, a DNA hypermethylation phenotype is observed in oncometabolite producing cancers. Our group has found that DNA hypermethylation results in silencing of nicotinate phosphoribosyl transferase (NAPRT). NAPRT is a rate-limiting enzyme in the Preiss-Handler pathway, which is vital for NAD+ biosynthesis. We have shown that the NAPRT gene is hypermethylated in regions surrounding and within a CpG island in the promoter. Hypermethylation of the NAPRT gene also occurs in patient tumor samples. Methylation of the promoter appears to control expression of mRNA and protein. We now show that silencing of NAPRT expression occurs in patient samples of oncometabolite-producing tumors. Furthermore, oncometabolite-producing cancer models that silence NAPRT are extremely sensitive to nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, which further prevents NAD+ biosynthesis via inhibition of the NAM Salvage Pathway. Furthermore, NAD+ is used to synthesize poly-ADP-ribose (PAR) chains by Poly (ADP-ribose) Polymerases (PARPs) to recruit other DNA damage response proteins, suggesting that NAMPTis and PARPis may synergize in oncometabolite-producing cancers. Ongoing studies are investigating the role of histone and DNA demethylating enzymes in NAPRT silencing and the efficacy of NAMPTis in NAPRT silenced models in vivo. Overall, our findings indicate that NAPRT-silencing can be therapeutically targeted in oncometabolite-producing cancers and elucidates how oncometabolite induced hypermethylation can impact diverse cellular processes from metabolism to DNA repair. Citation Format: Katelyn J. Noronha, Karlie N. Lucas, Sophia J. Zhao, Joseph Edmonds, Sam Friedman, Matthew A. Murray, Samantha Liu, Jiayu Liang, Sateja Paradkar, Hao Zeng, Ranjini K. Sundaram, Josh Spurrier, Mitch Raponi, Dipti Sajed, Brian M. Shuch, Juan C. Vasquez, Ranjit S. Bindra. NAPRT silencing in oncometabolite-producing cancers confers therapeutic vulnerabilities to NAD+ depletion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3086.