Overcoming Wnt-β-catenin dependent anticancer therapy resistance in leukaemia stem cells.
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.
Nature cell biology
Perry, J. M., Tao, F., Roy, A., Lin, T., He, X., Chen, S., Lu, X., Nemechek, J., Ruan, L., Yu, X., Dukes, D., Moran, A., Pace, J., Schroeder, K., Zhao, M., Venkatraman, A., Qian, P., Li, Z., Hembree, M., Paulson, A., He, Z., Xu, D., Tran, T., Deshmukh, P., Nguyen, C., Kasi, R., Ryan, R., Broward, M., Ding, S., Guest, E. M., August, K., Gamis, A. S., Godwin, A., Sittampalam, G., Weir, S. J., Li, L. Overcoming Wnt-β-catenin dependent anticancer therapy resistance in leukaemia stem cells. Nature cell biology 22, 689-700 (2020).