The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate‐limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for ...nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.
Synopsis
This study reports that AG636, an inhibitor of the metabolic enzyme DHODH, has excellent potency against acute myeloid leukemia (AML) in pre‐clinical models.
AG636 exhibits potent activity against different AML subtypes in vivo, promoting a combination of cell death and differentiation and effectively reducing leukemic stem cells.
DHODH inhibition has a moderate impact on normal blood development, but the effects are temporary with hematopoietic populations recovering after treatment cessation.
Pyrimidine starvation limits nascent protein synthesis, in part through downregulating YY1.
Loss of CDK5, a gene recurrently deleted in a subset of patients with aggressive disease, alters the molecular response of leukemic cells to AG636 and increases their sensitivity to drug treatment.
This study reports that AG636, an inhibitor of the metabolic enzyme DHODH, has excellent potency against acute myeloid leukemia (AML) in pre‐clinical models.
Approximately 20% of acute myeloid leukemia (AML) patients carry mutations in IDH1 or IDH2 that result in over-production of the oncometabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors ...that block 2-HG synthesis can induce complete morphological remission; however, almost all patients eventually acquire drug resistance and relapse. Using a multi-allelic mouse model of IDH1-mutant AML, we demonstrate that the clinical IDH1 inhibitor AG-120 (ivosidenib) exerts cell-type-dependent effects on leukemic cells, promoting delayed disease regression. Although single-agent AG-120 treatment does not fully eradicate the disease, it increases cycling of rare leukemia stem cells and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitizes IDH1-mutant AML to azacitidine, with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide a mechanistic rationale for the observed combinatorial effect of AG-120 and azacitidine in patients.
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•Inhibition of mutant IDH1 promotes exhaustion of the leukemic hierarchy•Resistance to the IDH1 inhibitor AG-120 can arise through transcriptional reprogramming•The differentiation state of AML cells affects their response to IDH1 inhibition•The response of LSCs to AG-120 sensitizes them to azacitidine
IDH1-mutant acute myeloid leukemia cells accumulate the oncometabolite D-2-hydroxyglutarate (2-HG). Gruber et al. demonstrate that pharmacological 2-HG blockade sensitizes rare leukemia stem cells to the cytosine analogue azacitidine by promoting cycling and upregulating pyrimidine salvage.
