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Cancer cell-autonomous cGAS-STING response confers drug resistance

Qian-Ming Lv, Shi-Yi Wang, Hui-Min Lei, Ke-Ren Zhang, Ya-Bin Tang, Ying Shen, Li-Ming Lu, Hong-Zhuan Chen, Liang Zhu
doi: https://doi.org/10.1101/2021.10.23.465546
Qian-Ming Lv
1Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Shi-Yi Wang
1Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Hui-Min Lei
1Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Ke-Ren Zhang
1Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Ya-Bin Tang
1Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Ying Shen
1Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Li-Ming Lu
3Shanghai Institute of Immunology, College of Basic Medical Sciences & Central laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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  • For correspondence: jyzhul@shsmu.edu.cn yaoli@shsmu.edu.cn lulunew2003@163.com
Hong-Zhuan Chen
2Department of Clinical Pharmacy, Institute of Interdisciplinary Integrative Biomedical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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  • For correspondence: jyzhul@shsmu.edu.cn yaoli@shsmu.edu.cn lulunew2003@163.com
Liang Zhu
1Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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  • For correspondence: jyzhul@shsmu.edu.cn yaoli@shsmu.edu.cn lulunew2003@163.com
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Abstract

As an evolutionarily conserved DNA-sensing machinery in innate immunity, the cGAS-STING pathway has been reported to play an important role in immune surveillance and tumor suppression. Recent evidence suggests an intriguing tumor- and metastasis-promoting effect of this signaling pathway, either in a cancer cell-autonomous or a cancer cell-nonautonomous, bystander cell-mediated manner. Here, we show a new face of cGAS-STING signaling whose activation in a cancer-cell-autonomous response manner confers drug resistance. Targeted or conventional chemotherapy drug treatment induced cancer cell cytosolic DNA accumulation and triggered subsequent cGAS-STING signaling activation in cancer cell lines and the human cell-derived xenograft tumors. This activation promoted an acquisition and maintenance of drug resistance which was prevented and overcome in vitro and in vivo by blockade of STING signaling. This finding highlights a new face of cGAS-STING signaling and an ability of cancer cells to hijack the evolutionarily conserved inflammatory signaling to counteract drug stress and warrants a caution in combining STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.

Statement of significance cGAS-STING signaling has long been recognized as playing a key role in triggering antitumor immunity. We reveal a new face of cGAS-STING signaling and an ability of cancer cells autonomously to hijack the evolutionarily conserved inflammatory signaling to counteract drug stress.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Conflicts of interest, The authors declare that they have no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 23, 2021.
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Cancer cell-autonomous cGAS-STING response confers drug resistance
Qian-Ming Lv, Shi-Yi Wang, Hui-Min Lei, Ke-Ren Zhang, Ya-Bin Tang, Ying Shen, Li-Ming Lu, Hong-Zhuan Chen, Liang Zhu
bioRxiv 2021.10.23.465546; doi: https://doi.org/10.1101/2021.10.23.465546
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Cancer cell-autonomous cGAS-STING response confers drug resistance
Qian-Ming Lv, Shi-Yi Wang, Hui-Min Lei, Ke-Ren Zhang, Ya-Bin Tang, Ying Shen, Li-Ming Lu, Hong-Zhuan Chen, Liang Zhu
bioRxiv 2021.10.23.465546; doi: https://doi.org/10.1101/2021.10.23.465546

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