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Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells
Perry, John M. Tao, Fang Roy, Anuradha Lin, Tara He, Xi C. Chen, Shiyuan Lu, Xiuling Nemechek, Jacqelyn Ruan, Linhao Yu, Xiazhen
Perry, John M.
Tao, Fang
Roy, Anuradha
Lin, Tara
He, Xi C.
Chen, Shiyuan
Lu, Xiuling
Nemechek, Jacqelyn
Ruan, Linhao
Yu, Xiazhen
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Abstract
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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Date
2020-04-20
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Publisher
Nature Research
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Keywords
Cancer immunotherapy, Cancer stem cells, Cancer therapeutic resistance, Cell signaling
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