Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells
Emily Gruber, Joan So, Alexander C. Lewis, Rheana Franich, Rachel M. Cole, Luciano G. Martelotto, Amy J. Rogers, Eva Vidacs, Peter Fraser, Kym L. Stanley, Lisa D. Jones, Anna Trigos, Niko Thio, Jason Li, Brandon Nicolay, Scott R. Daigle, Adriana E. Tron, Marc L. Hyer, Jake Shortt, Ricky W. Johnstone, Lev M. Kats
Abstract
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.