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NAPRT Silencing in FH-Deficient Renal Cell Carcinoma Confers Therapeutic Vulnerabilities via NAD+ Depletion
Katelyn J Noronha1, Karlie N Lucas2, Sateja Paradkar3
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut.
Abstract:
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.
Insights
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) involves fumarate hydratase (FH) mutations. FH loss causes fumarate buildup, leading to DNA hypermethylation and silencing of NAPRT, making cancers sensitive to NAMPT inhibitors.
Area of Science:
- Oncology
- Cancer Metabolism
- Epigenetics
Background:
- Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is linked to fumarate hydratase (FH) gene mutations.
- Loss of FH function leads to fumarate accumulation, an oncometabolite that disrupts cellular processes and promotes tumor growth.
- Fumarate accumulation can inhibit TET enzymes, leading to DNA hypermethylation.
Purpose of the Study:
- To investigate hypermethylation patterns in FH-mutant cancers.
- To identify novel therapeutic targets in HLRCC and other oncometabolite-producing cancers.
- To explore the role of nicotinate phosphoribosyl transferase (NAPRT) in FH-deficient renal cell carcinoma (RCC).
Main Methods:
- Analysis of FH-mutant cell lines and tumor samples for hypermethylation patterns.
- Assessment of nicotinate phosphoribosyl transferase (NAPRT) expression and promoter methylation.
- Evaluation of sensitivity to nicotinamide phosphoribosyl transferase inhibitors (NAMPTi) and PARP inhibitors in FH-deficient RCC models with NAPRT silencing.
Main Results:
- Hypermethylation in FH-mutant cancers is associated with the silencing of NAPRT, a key enzyme in NAD+ biosynthesis.
- NAPRT promoter hypermethylation leads to loss of NAPRT expression in FH-deficient RCC models.
- FH-deficient RCC models and other oncometabolite-producing cancers with NAPRT silencing show extreme sensitivity to NAMPT inhibitors.
- Combined treatment with NAMPT inhibitors and PARP inhibitors demonstrated synergistic tumor cell killing, impacting PAR-mediated DNA repair.
Conclusions:
- NAPRT silencing is a therapeutically relevant vulnerability in oncometabolite-producing cancers, including FH-deficient HLRCC.
- NAPRT serves as a potential biomarker for targeting NAD+ metabolism with NAMPT inhibitors in HLRCC.
- Combining NAMPT inhibitors with PARP inhibitors offers a strategy for targeting DNA repair processes in these cancers.
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