NAPRT Silencing in FH-Deficient Renal Cell Carcinoma Confers Therapeutic Vulnerabilities via NAD+ Depletion.

Autor: Noronha KJ; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut., Lucas KN; Department of Therapeutic Radiology, Yale University, New Haven, Connecticut., Paradkar S; Department of Experimental Pathology, Yale University, New Haven, Connecticut., Edmonds J; Department of Therapeutic Radiology, Yale University, New Haven, Connecticut., Friedman S; Department of Therapeutic Radiology, Yale University, New Haven, Connecticut., Murray MA; Department of Experimental Pathology, Yale University, New Haven, Connecticut., Liu S; Department of Therapeutic Radiology, Yale University, New Haven, Connecticut., Sajed DP; Department of Pathology, University of California Los Angeles, Los Angeles, California., Sachs C; Department of Pathology, University of California Los Angeles, Los Angeles, California., Spurrier J; Alphina Therapeutics, New Haven, Connecticut., Raponi M; Alphina Therapeutics, New Haven, Connecticut., Liang J; Department of Urology, West China Hospital, Sichuan University, Chengdu, P.R. China., Zeng H; Department of Urology, West China Hospital, Sichuan University, Chengdu, P.R. China., Sundaram RK; Department of Therapeutic Radiology, Yale University, New Haven, Connecticut., Shuch B; Institute of Urologic Oncology, Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California., Vasquez JC; Department of Pediatric Hematology and Oncology, Yale University, New Haven, Connecticut., Bindra RS; Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
Jazyk: angličtina
Zdroj: Molecular cancer research : MCR [Mol Cancer Res] 2024 Oct 02; Vol. 22 (10), pp. 973-988.
DOI: 10.1158/1541-7786.MCR-23-1003
Abstrakt: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. Loss of FH leads to accumulation of fumarate, an oncometabolite that disrupts multiple cellular processes and drives tumor progression. High levels of fumarate inhibit alpha ketoglutarate-dependent dioxygenases, including the ten-eleven translocation (TET) enzymes, and can lead to global DNA hypermethylation. Here, we report patterns of hypermethylation in FH-mutant cell lines and tumor samples are associated with the silencing of nicotinate phosphoribosyl transferase (NAPRT), a rate-limiting enzyme in the Preiss-Handler pathway of NAD+ biosynthesis, in a subset of HLRCC cases. NAPRT is hypermethylated at a CpG island in the promoter in cell line models and patient samples, resulting in loss of NAPRT expression. We find that FH-deficient RCC models with loss of NAPRT expression, as well as other oncometabolite-producing cancer models that silence NAPRT, are extremely sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTi). NAPRT silencing was also associated with synergistic tumor cell killing with PARP inhibitors and NAMPTis, which was associated with effects on PAR-mediated DNA repair. Overall, our findings indicate that NAPRT silencing can be targeted in oncometabolite-producing cancers and elucidates how oncometabolite-associated hypermethylation can impact diverse cellular processes and lead to therapeutically relevant vulnerabilities in cancer cells. Implications: NAPRT is a novel biomarker for targeting NAD+ metabolism in FH-deficient HLRCCs with NAMPTis alone and targeting DNA repair processes with the combination of NAMPTis and PARP inhibitors.
(©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze: MEDLINE