Abstract IA016: Remodeling of tumor metabolism by L-2-hydroxyglutarate: Implications for renal cancer growth and progression

Abstract Tumor cells remodel their metabolism to meet their unique demands in order to support tumor growth and progression. However, this reprogramming may create metabolic vulnerabilities. The small molecule L-2-hdroxyglutarate (L-2HG) is commonly elevated in clear cell renal cell carcinoma (ccRCC). Similar to other small molecules elevated in cancer, L-2HG has the potential to regulate gene expression by altering DNA, histone, and/or RNA methylation. Using unbiased profiling methodologies, we find that L-2HG remodels tumoral metabolism in renal cancer cells through the combined effects on histone methylation and RNA N6-methyladenosine (m6A). The combined effects of L-2HG result in a serine liability that renders tumors cells reliant on exogenous serine to support in vitro/vivo tumor growth and redox balance. In agreement with these data, raised L-2HG kidney tumors have reduced expression of serine biosynthetic enzymes. In summary, our data reveal that high L-2HG kidney tumors could be targeted by strategies that limit the availability of this now "essential" amino acid. Citation Format: Sunil Sudarshan. Remodeling of tumor metabolism by L-2-hydroxyglutarate: Implications for renal cancer growth and progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA016.