期刊
NATURE CELL BIOLOGY
卷 22, 期 6, 页码 689-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41556-020-0507-y
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资金
- NIH [R01 GM100701]
- National Science Foundation NSF CAREER Award [DMR-0748398]
- ACS [PRF 5247200]
- Academic Plan Grant from the University of Connecticut
- University of Kansas Cancer Center's Cancer Center Support Grant [P30 CA168524]
- Stowers Institute for Medical Research
- Children's Mercy Kansas City
- Braden's Hope for Childhood Cancer
- Leukemia and Lymphoma Society (LLS)
- Kansas Bioscience Authority
- Hall Family Foundation
- University of Kansas Cancer Center (KUCC) National Cancer Institute Cancer Center Support Grant (NCI-CCSG) [P30 CA168524]
Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-beta-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate beta-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-beta-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated beta-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, beta-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated beta-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape. Targeting resistant stem cells in leukaemia, Perry et al. show that doxorubicin at low doses decreases Akt-mediated beta-catenin activity, downregulates expression of multiple immune-checkpoint genes and dampens tumorigenesis of leukaemia stem cells.
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