| Literature DB >> 32313104 |
John M Perry1,2,3,4, Fang Tao1,2, Anuradha Roy5, Tara Lin3, Xi C He1, Shiyuan Chen1, Xiuling Lu6, Jacqelyn Nemechek2, Linhao Ruan1,7, Xiazhen Yu1,8, Debra Dukes1, Andrea Moran1, Jennifer Pace2, Kealan Schroeder2, Meng Zhao1,9, Aparna Venkatraman1, Pengxu Qian1,10,11, Zhenrui Li1,12, Mark Hembree1, Ariel Paulson1, Zhiquan He13, Dong Xu13, Thanh-Huyen Tran6,14, Prashant Deshmukh15, Chi Thanh Nguyen16, Rajeswari M Kasi15,16, Robin Ryan2, Melinda Broward3, Sheng Ding17, Erin Guest2, Keith August2, Alan S Gamis2, Andrew Godwin3, G Sitta Sittampalam3,18, Scott J Weir19, Linheng Li20,21.
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.Entities:
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Year: 2020 PMID： 32313104 PMCID： PMC8010717 DOI： 10.1038/s41556-020-0507-y
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.824