Perry, John M.Tao, FangRoy, AnuradhaLin, TaraHe, Xi C.Chen, ShiyuanLu, XiulingNemechek, JacqelynRuan, LinhaoYu, XiazhenDukes, DebraMoran, AndreaPace, JenniferSchroeder, KealanZhao, MengVenkatraman, AparnaQian, PengxuLi, ZhenruiHembree, MarkPaulson, ArielHe, ZhiquanXu, DongTran, Thanh-HuyenDeshmukh, PrashantNguyen, Chi ThanhKasi, Rajeswari M.Ryan, RobinBroward, MelindaDing, ShengGuest, ErinAugust, KeithGamis, Alan S.Godwin, AndrewSittampalam, G. SittaWeir, Scott J.Li, Linheng2022-02-042022-02-042020-04-20Perry, 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-yhttps://hdl.handle.net/1808/32489Leukaemia 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.Copyright © 2020, The Author(s), under exclusive license to Springer Nature Limited.Cancer immunotherapyCancer stem cellsCancer therapeutic resistanceCell signalingArticle10.1038/s41556-020-0507-yPMC8010717openAccess