Abstract 20910: Alpha-Ketoglutarate Metabolism Regulates Oncometabolic Adaptation in the Heart

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Introduction: The term “cancer and the heart” traditionally refers to the cardiotoxic effects of chemotherapeutic agents. However, independent of any cytostatic treatment cancer survivors have a five-fold higher risk for developing heart failure. Therefore, new therapeutic strategies must consider tumor biology when aiming at protecting the heart. In isocitrate dehydrogenase (IDH)1 and 2 mutant tumors, the elevated production of the oncometabolite D-2-hydroxyglutarate (D2-HG) is associated with systemic effects, including dilated cardiomyopathy. About 20% of acute myeloid leukemia cases harbor mutations of the IDH, which leads to reduced patient survival and causes metabolic dysfunction through production of the oncometabolite D2-HG. Recent findings have shown that D2-HG impairs oxidative decarboxylation of α-KG, which in turn increases ATP citrate lyase activity.

Hypothesis: Based on these findings we are now proposing that modulation of ACL activity reverses D2-HG mediated metabolic changes.

Methods: As models we used isolated working rat hearts; and combined C13-tracer studies with computational flux analysis.

Results: Wild type rat hearts were perfused with the ACL inhibitor BMS303141 (0.5 μM; BMS) or D2-HG (1 mM). Cardiac power rapidly declined by 25% in the presence of BMS or D2-HG alone. Simultaneous perfusion with D2-HG and BMS, improved cardiac power, suggesting that modulation of ACL improves cardiac function only in presence of D2-HG. Further, α-KG dehydrogenase (α-KGDH) activity increased with ACL inhibition, reflecting an inverse relationship between these enzymes. Computational flux analysis using the metabolic genome-scale network CardioNet revealed that D2-HG-dependent inhibition by α-KGDH shifts cardiac metabolism towards increased reductive carboxylation of α-KG.

Conclusions: Our findings suggest an “oncometabolic axis” in the heart and underscore the potential application of ACL inhibitors to protect the heart from failing in IDH-mutant tumors.

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