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Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells
dc.contributor.author | Perry, John M. | |
dc.contributor.author | Tao, Fang | |
dc.contributor.author | Roy, Anuradha | |
dc.contributor.author | Lin, Tara | |
dc.contributor.author | He, Xi C. | |
dc.contributor.author | Chen, Shiyuan | |
dc.contributor.author | Lu, Xiuling | |
dc.contributor.author | Nemechek, Jacqelyn | |
dc.contributor.author | Ruan, Linhao | |
dc.contributor.author | Yu, Xiazhen | |
dc.contributor.author | Dukes, Debra | |
dc.contributor.author | Moran, Andrea | |
dc.contributor.author | Pace, Jennifer | |
dc.contributor.author | Schroeder, Kealan | |
dc.contributor.author | Zhao, Meng | |
dc.contributor.author | Venkatraman, Aparna | |
dc.contributor.author | Qian, Pengxu | |
dc.contributor.author | Li, Zhenrui | |
dc.contributor.author | Hembree, Mark | |
dc.contributor.author | Paulson, Ariel | |
dc.contributor.author | He, Zhiquan | |
dc.contributor.author | Xu, Dong | |
dc.contributor.author | Tran, Thanh-Huyen | |
dc.contributor.author | Deshmukh, Prashant | |
dc.contributor.author | Nguyen, Chi Thanh | |
dc.contributor.author | Kasi, Rajeswari M. | |
dc.contributor.author | Ryan, Robin | |
dc.contributor.author | Broward, Melinda | |
dc.contributor.author | Ding, Sheng | |
dc.contributor.author | Guest, Erin | |
dc.contributor.author | August, Keith | |
dc.contributor.author | Gamis, Alan S. | |
dc.contributor.author | Godwin, Andrew | |
dc.contributor.author | Sittampalam, G. Sitta | |
dc.contributor.author | Weir, Scott J. | |
dc.contributor.author | Li, Linheng | |
dc.date.accessioned | 2022-02-04T14:54:07Z | |
dc.date.available | 2022-02-04T14:54:07Z | |
dc.date.issued | 2020-04-20 | |
dc.identifier.citation | Perry, J.M., Tao, F., Roy, A. et al. Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells. Nat Cell Biol 22, 689–700 (2020). https://doi.org/10.1038/s41556-020-0507-y | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/32489 | |
dc.description.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. | en_US |
dc.publisher | Nature Research | en_US |
dc.rights | Copyright © 2020, The Author(s), under exclusive license to Springer Nature Limited. | en_US |
dc.subject | Cancer immunotherapy | en_US |
dc.subject | Cancer stem cells | en_US |
dc.subject | Cancer therapeutic resistance | en_US |
dc.subject | Cell signaling | en_US |
dc.title | Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Roy, Anuradha | |
kusw.kudepartment | High Throughput Screening Laboratory | en_US |
dc.identifier.doi | 10.1038/s41556-020-0507-y | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC8010717 | en_US |
dc.rights.accessrights | openAccess | en_US |