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

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.

Authors

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, Sitta; Weir, Scott J; Li, Linheng;

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