The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia.
Cell Rep. 2022 Aug 16;40(7):111182. doi: 10.1016/j.celrep.2022.111182.
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.
约 20%的急性髓系白血病（AML）患者存在 IDH1 或 IDH2 突变，导致致癌代谢物 D-2-羟戊二酸（2-HG）的过度产生。抑制 2-HG 合成的小分子抑制剂可诱导完全形态缓解；然而，几乎所有患者最终都会产生耐药性并复发。使用多等位基因 IDH1 突变型 AML 小鼠模型，我们证明了临床 IDH1 抑制剂 AG-120（ivosidenib）对白血病细胞具有细胞类型依赖性的作用，促进疾病的延迟消退。尽管单药 AG-120 治疗不能完全消除疾病，但它增加了罕见白血病干细胞的循环，并触发嘧啶补救途径的转录上调。因此，AG-120 使 IDH1 突变型 AML 对阿扎胞苷敏感，AG-120 与阿扎胞苷的联合在体内显示出极大改善的疗效。我们的数据强调了非遗传异质性对治疗反应的影响，并为观察到的 AG-120 和阿扎胞苷在患者中的组合效应提供了机制上的依据。
