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-beta-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 beta-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-beta-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated beta-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, beta-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 beta-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 beta-catenin activity, downregulates expression of multiple immune-checkpoint genes and dampens tumorigenesis of leukaemia stem cells.