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WEE1 inhibitor and ataxia telangiectasia and RAD3‐related inhibitor trigger stimulator of interferon gene‐dependent immune response and enhance tumor treatment efficacy through programmed death‐ligand 1 blockade
WEE1 plays an important role in the regulation of cell cycle G2/M checkpoints and DNA damage response (DDR). Inhibition of WEE1 can increase the instability of the genome and have anti–tumor effects in some solid tumors. However, it has certain limitations for multiple cancer cells from different li...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586668/ https://www.ncbi.nlm.nih.gov/pubmed/34382294 http://dx.doi.org/10.1111/cas.15108 |
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author | Wu, Xue Kang, Xiaoyan Zhang, Xiaoxiao Xie, Wan Su, Yue Liu, Xiaoyu Guo, Lili Guo, Ensong Li, Fuxia Hu, Dianxing Qin, Xu Fu, Yu Peng, Wenju Jia, Jiedong Wang, Changyu |
author_facet | Wu, Xue Kang, Xiaoyan Zhang, Xiaoxiao Xie, Wan Su, Yue Liu, Xiaoyu Guo, Lili Guo, Ensong Li, Fuxia Hu, Dianxing Qin, Xu Fu, Yu Peng, Wenju Jia, Jiedong Wang, Changyu |
author_sort | Wu, Xue |
collection | PubMed |
description | WEE1 plays an important role in the regulation of cell cycle G2/M checkpoints and DNA damage response (DDR). Inhibition of WEE1 can increase the instability of the genome and have anti–tumor effects in some solid tumors. However, it has certain limitations for multiple cancer cells from different lineages. Therefore, we consider the use of synthetic lethal interactions to enhance the therapeutic effect. Our experiments proved that WEE1 inhibitor (WEE1i) can activate the ataxia telangiectasia and RAD3‐related (ATR) pathway and that blockage of ATR dramatically sensitized the WEE1i‐induced cell death. The tumor‐selective synthetic lethality between bioavailable WEE1 and ATR inhibitors led to tumor remission in vivo. Mechanistically, the combination promoted the accumulation of cytosolic double‐strand DNA, which subsequently activated the stimulator of the interferon gene (STING) pathway and induced the production of type I interferon and CD8+ T cells, thereby inducing anti–tumor immunity. Furthermore, our study found that immune checkpoint programmed death‐ligand 1 is upregulated by the combination therapy, and blocking PD‐L1 further enhances the effect of the combination therapy. In summary, as an immunomodulator, the combination of WEE1i with ATR inhibitor (ATRi) and immune checkpoint blockers provides a potential new approach for cancer treatment. |
format | Online Article Text |
id | pubmed-8586668 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85866682021-11-18 WEE1 inhibitor and ataxia telangiectasia and RAD3‐related inhibitor trigger stimulator of interferon gene‐dependent immune response and enhance tumor treatment efficacy through programmed death‐ligand 1 blockade Wu, Xue Kang, Xiaoyan Zhang, Xiaoxiao Xie, Wan Su, Yue Liu, Xiaoyu Guo, Lili Guo, Ensong Li, Fuxia Hu, Dianxing Qin, Xu Fu, Yu Peng, Wenju Jia, Jiedong Wang, Changyu Cancer Sci Original Articles WEE1 plays an important role in the regulation of cell cycle G2/M checkpoints and DNA damage response (DDR). Inhibition of WEE1 can increase the instability of the genome and have anti–tumor effects in some solid tumors. However, it has certain limitations for multiple cancer cells from different lineages. Therefore, we consider the use of synthetic lethal interactions to enhance the therapeutic effect. Our experiments proved that WEE1 inhibitor (WEE1i) can activate the ataxia telangiectasia and RAD3‐related (ATR) pathway and that blockage of ATR dramatically sensitized the WEE1i‐induced cell death. The tumor‐selective synthetic lethality between bioavailable WEE1 and ATR inhibitors led to tumor remission in vivo. Mechanistically, the combination promoted the accumulation of cytosolic double‐strand DNA, which subsequently activated the stimulator of the interferon gene (STING) pathway and induced the production of type I interferon and CD8+ T cells, thereby inducing anti–tumor immunity. Furthermore, our study found that immune checkpoint programmed death‐ligand 1 is upregulated by the combination therapy, and blocking PD‐L1 further enhances the effect of the combination therapy. In summary, as an immunomodulator, the combination of WEE1i with ATR inhibitor (ATRi) and immune checkpoint blockers provides a potential new approach for cancer treatment. John Wiley and Sons Inc. 2021-08-31 2021-11 /pmc/articles/PMC8586668/ /pubmed/34382294 http://dx.doi.org/10.1111/cas.15108 Text en © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Wu, Xue Kang, Xiaoyan Zhang, Xiaoxiao Xie, Wan Su, Yue Liu, Xiaoyu Guo, Lili Guo, Ensong Li, Fuxia Hu, Dianxing Qin, Xu Fu, Yu Peng, Wenju Jia, Jiedong Wang, Changyu WEE1 inhibitor and ataxia telangiectasia and RAD3‐related inhibitor trigger stimulator of interferon gene‐dependent immune response and enhance tumor treatment efficacy through programmed death‐ligand 1 blockade |
title | WEE1 inhibitor and ataxia telangiectasia and RAD3‐related inhibitor trigger stimulator of interferon gene‐dependent immune response and enhance tumor treatment efficacy through programmed death‐ligand 1 blockade |
title_full | WEE1 inhibitor and ataxia telangiectasia and RAD3‐related inhibitor trigger stimulator of interferon gene‐dependent immune response and enhance tumor treatment efficacy through programmed death‐ligand 1 blockade |
title_fullStr | WEE1 inhibitor and ataxia telangiectasia and RAD3‐related inhibitor trigger stimulator of interferon gene‐dependent immune response and enhance tumor treatment efficacy through programmed death‐ligand 1 blockade |
title_full_unstemmed | WEE1 inhibitor and ataxia telangiectasia and RAD3‐related inhibitor trigger stimulator of interferon gene‐dependent immune response and enhance tumor treatment efficacy through programmed death‐ligand 1 blockade |
title_short | WEE1 inhibitor and ataxia telangiectasia and RAD3‐related inhibitor trigger stimulator of interferon gene‐dependent immune response and enhance tumor treatment efficacy through programmed death‐ligand 1 blockade |
title_sort | wee1 inhibitor and ataxia telangiectasia and rad3‐related inhibitor trigger stimulator of interferon gene‐dependent immune response and enhance tumor treatment efficacy through programmed death‐ligand 1 blockade |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586668/ https://www.ncbi.nlm.nih.gov/pubmed/34382294 http://dx.doi.org/10.1111/cas.15108 |
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