Catabolic Flexibility Enhances Drug Resistance but Induces Selective Vulnerability to New Mitochondrial-Targeted Therapeutic Combinations in IDH Mutant Leukemia

Isocitrate dehydrogenases IDH1/2 mutations and its oncometabolite 2-HG have been of major clinical interest as they have been causally linked to the development of glioma and acute myeloid leukemia (AML). However, global impact of mutations in these two key metabolic enzymes on cellular metabolic networks and chemoresistance is not well defined. We hypothesized that key metabolic fluxes are selectively reprogrammed to maintain biosynthetic homeostasis and chemoresistance in IDH mutant acute myeloid leukemia cells. We show that metabolic reprogramming initiated by IDH1 mutation leads to marked increases in glucose, glutamine and fatty acid catabolism that along with enhancement of wild-type IDH enzyme activity contribute to provision of α-KG required for 2-HG synthesis and to replenish Krebs cycle intermediates for biosynthetic reactions, oxygen consumption and ATP production. Mechanistically, this occurs through both 2-HG-dependent histone methylation-driven CEBPα activation of FAO and reprogramming of systemic metabolic fluxes through other pathways that augment catabolic flexibility. This catabolic flexibility leads to the enhancement of Krebs cycle and OxPHOS activities that are not necessarily rescued by IDH mutant inhibitors. Similarly, generation of 2-HG reflects the catabolic flexibility of IDH1 mutant cells but its reduction does not necessarily reverse the mitochondrial OxPHOS phenotype or reduce cell proliferation and survival in IDH1 mutant cells. This also renders IDH1 mutant cells more resistant to conventional chemotherapy such as cytarabine. While catabolic flexibility is not druggable per se, its metabolic consequence (e.g. enhanced mitochondrial dependency) is a specifically targetable vulnerability in IDH1 mutant AML and mutant cells are more susceptible to mitochondrial inhibition by OxPHOSi (IACS-107839) and BCL2i (ABT-199) compared to WT cells. Treatment with mutant IDH1-specific inhibitors enhances anti-leukemic effects of OxPHOS inhibitors alone and in combination with cytarabine. Our findings also provide a strong scientific rationale for innovative combinatory targeted therapies to treat this subgroup of patients, especially those unresponsive to or relapsing from IDH mutant-specific inhibitors.