Abstract SY19-01: Metabolic consequences and liabilities of TCA cycle truncation in cancer

Abstract

Abstract Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tricarboxylic acid (TCA) cycle enzymes while SDH is also part of the respiratory chain. Despite their key housekeeping activities, the genetic loss of FH or of any of the SDH subunits is associated with susceptibility to cancers. SDH or FH inactivation leads to the accumulation of metabolites which cause the activation of hypoxia-inducible factors and the inhibition of histone and DNA demethylases, establishing pseudohypoxic and hypermethylator phenotype. However, surviving the loss of these essential metabolic enzymes requires a significant metabolic adaptation as backup mechanisms for the dysfunctional TCA cycle and oxidative phosphorylation in these tumors. Identifying these adaptations would reveal effective and specific metabolic vulnerabilities which can serve as potential molecular targets for therapeutic intervention. We have identified in the past a few metabolic essentialities in cells deficient in FH and SDH and now performed a pharmacologic phenotypic synthetic lethal screen to identified effective drugs that specifically kill SDH- and FH-deficient cells. Utilizing metabolomics, we have delineated the molecular target of the effective compounds. Citation Format: Eyal Gottlieb. Metabolic consequences and liabilities of TCA cycle truncation in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY19-01.