Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nat Commun. 2021 May 10;12(1):2607. doi: 10.1038/s41467-021-22874-x.
Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.
突变 IDH1 或 IDH2 的别构抑制剂诱导突变白血病细胞的终末分化，并在大约 40%的具有突变的急性髓系白血病 (AML) 患者中提供持久的临床反应。然而，对药物的原发性耐药和获得性耐药是主要的临床问题。为了了解对 IDH 抑制剂 (IDHi) 的临床耐药的分子基础，我们对 60 名接受抑制剂治疗的 IDH1 或 IDH2 突变 AML 患者的纵向采集标本进行了多方面的基因组分析（DNA 测序、RNA 测序和胞嘧啶甲基化分析）。分析表明，白血病干性是对 IDHi 原发性耐药的主要驱动因素，而 RUNX1/CEBPA 或 RAS-RTK 通路基因的突变选择是对 IDHi 获得性耐药的主要驱动因素，同时还有 BCOR、同源 IDH 基因和 TET2。这些数据表明，靶向干性和某些高危共存突变可能克服 AML 中对 IDHi 的耐药性。
