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

• Published in: Nature cell biology Vol. 22; no. 6; pp. 689 - 700
• Main 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, G. Sitta, Weir, Scott J., Li, Linheng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2020; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/31; 45; 45/100; 45/15; 59; 631/532/71; 631/80/86; 64; 64/60; 692/699/67/1059/2325; 692/699/67/1059/2326; AKT protein; Animals; Antibiotics, Antineoplastic - pharmacology; Apoptosis; beta Catenin - physiology; Biomedical and Life Sciences; Cancer Research; Cancer therapies; Cell Biology; Cell Proliferation; Chemotherapy; Cytotoxicity; Developmental Biology; Doxorubicin; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Female; Gene expression; High-throughput screening; Humans; Immune checkpoint; Inhibitors; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Life Sciences; Male; Mice; Mice, Knockout; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; PD-L1 protein; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Progenitor cells; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - physiology; Stem cell transplantation; Stem Cells; Tumor Cells, Cultured; Tumorigenesis; Wnt protein; Wnt Proteins - physiology; Xenograft Model Antitumor Assays; β-Catenin
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-020-0507-y

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. Targeting resistant stem cells in leukaemia, Perry et al. show that doxorubicin at low doses decreases Akt-mediated β-catenin activity, downregulates expression of multiple immune-checkpoint genes and dampens tumorigenesis of leukaemia stem cells.