Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells

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Issue Date
2020-04-20Author
Perry, John M.
Tao, Fang
Roy, Anuradha
Lin, Tara
He, Xi C.
Chen, Shiyuan
Lu, Xiuling
Nemechek, Jacqelyn
Ruan, Linhao
Yu, Xiazhen
Dukes, Debra
Moran, Andrea
Pace, Jennifer
Schroeder, Kealan
Zhao, Meng
Venkatraman, Aparna
Qian, Pengxu
Li, Zhenrui
Hembree, Mark
Paulson, Ariel
He, Zhiquan
Xu, Dong
Tran, Thanh-Huyen
Deshmukh, Prashant
Nguyen, Chi Thanh
Kasi, Rajeswari M.
Ryan, Robin
Broward, Melinda
Ding, Sheng
Guest, Erin
August, Keith
Gamis, Alan S.
Godwin, Andrew
Sittampalam, G. Sitta
Weir, Scott J.
Li, Linheng
Publisher
Nature Research
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
Copyright © 2020, The Author(s), under exclusive license to Springer Nature Limited.
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Show full item recordAbstract
Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt–β-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 β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt–β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-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 β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.
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Citation
Perry, J.M., Tao, F., Roy, A. et al. Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells. Nat Cell Biol 22, 689–700 (2020). https://doi.org/10.1038/s41556-020-0507-y
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