期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-22874-x
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资金
- Cancer Prevention Research Institute of Texas [R120501]
- Welch Foundation [G-0040]
- UT System STARS Award [PS100149]
- Khalifa Scholar Award
- Physician Scientist Program at MD Anderson
- V Foundation Lloyd Family Clinical Scholar Award
- Charif Souki Cancer Research Fund
- MD Anderson Cancer Center Leukemia SPORE [P50 CA100632]
- MD Anderson Cancer Center Support Grant (NIH) [P30 CA016672]
- Lynda Hill Foundation
- JSPS Overseas Research Fellowship
The authors found that stemness features are the major drivers of primary resistance to IDH inhibitors, while high-risk mutations are the main drivers of acquired resistance. Targeting stemness and certain high-risk co-occurring mutations may help overcome resistance to IDH inhibitors in AML.
The regulation of resistance to IDH inhibitors in acute myeloid leukaemia is not completely understood. Here the authors reveal with integrative multi-omics analyses that stemness features are major drivers of primary resistance, while high-risk mutations drive acquired resistance. 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.
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