Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability

Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identifi ed a lipid synthesis enzyme [acetyl CoA carboxylase 1 (ACC1)] as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identi-fied an mIDH1-specifi c reduction in fatty acids. mIDH1 also induced a switch to b -oxidation indicating reprogramming of metabolism toward a reliance on fatty acids. Compared with mIDH2, mIDH1 AML dis-played depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specifi c inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34 + hematopoietic stem/progenitor cells or mIDH2 AML. Genetic and pharmaco-logic targeting of ACC1 resulted in the growth inhibition of mIDH1 cancers not reversible by ivosidenib. Critically, the pharmacologic targeting of ACC1 improved the sensitivity of mIDH1 AML to venetoclax.

Automated summary

Isocitrate dehydrogenase 1 and 2 (IDH) mutations drive the production of (R)-2-hydroxyglutarate (2HG) in multiple cancers. A lipid synthesis enzyme, acetyl CoA carboxylase 1 (ACC1), was identified as a synthetic lethal target in mutant IDH1 (mIDH1) cancers. mIDH1 AML exhibits specific metabolic alterations, such as reduced fatty acids and a switch to fatty acid oxidation. Targeting ACC1 inhibits the growth of mIDH1 cancers and improves the sensitivity of mIDH1 AML to venetoclax.