ARID1B Deficiency Leads to Impaired DNA Damage Response and Activated cGAS-STING Pathway in Non-Small Cell Lung Cancer

Zhu, Guangsheng; Liu, Jinghao; Li, Yongwen; Huang, Hua; Chen, Chen; Wu, Di; Cao, Peijun; Su, Lianchun; Wang, Yanan; Zhang, Hongbing; Liu, Hongyu; Chen, Jun

doi:10.7150/jca.91955

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J Cancer 2024; 15(9):2601-2612. doi:10.7150/jca.91955 This issue Cite

Research Paper

ARID1B Deficiency Leads to Impaired DNA Damage Response and Activated cGAS-STING Pathway in Non-Small Cell Lung Cancer

Guangsheng Zhu^1#, Jinghao Liu^1#, Yongwen Li^2#, Hua Huang¹, Chen Chen², Di Wu¹, Peijun Cao¹, Lianchun Su^1,2, Yanan Wang¹, Hongbing Zhang¹, Hongyu Liu^2✉, Jun Chen^1,2✉

1. Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China.
2. Tianjin Lung Cancer Institute, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China.
^#These authors contributed equally in this work.

Citation:

Zhu G, Liu J, Li Y, Huang H, Chen C, Wu D, Cao P, Su L, Wang Y, Zhang H, Liu H, Chen J. ARID1B Deficiency Leads to Impaired DNA Damage Response and Activated cGAS-STING Pathway in Non-Small Cell Lung Cancer. J Cancer 2024; 15(9):2601-2612. doi:10.7150/jca.91955. https://www.jcancer.org/v15p2601.htm

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Abstract

Purpose: Lung cancer is a major cause of morbidity and mortality globally, necessitating the identification of predictive markers for effective immunotherapy. Mutations in SWI/SNF chromatin remodeling complex genes were reported sensitized human tumors to immune checkpoint inhibitors (ICIs), but the underlying mechanisms are unclear. This study aims to investigate the association between SWI/SNF gene ARID1B mutation and ICI response in non-small cell lung cancer (NSCLC) patients, to explore the functional consequences of ARID1B mutation on DNA damage response, immune microenvironment, and cGAS-STING pathway activation.

Methods: TCGA LUAD, LUSC, and AACR GENIE data are analyzed to assess ARID1B mutation status in NSCLC patients. Prognostic analysis evaluates the effect of ARID1B mutation on patient outcomes. In vitro experiments carried to investigate the consequences of ARID1B knockdown on DNA damage response and repair. The immune microenvironment is assessed based on ARID1B expression, and the relationship between ARID1B and the cGAS-STING pathway is explored.

Results: ARID1B mutation frequency is 5.7% in TCGA databases and 4.4% in the AACR GENIE project. NSCLC patients with ARID1B mutation showed improved overall and progression-free survival following ICIs treatment. ARID1B knockdown in lung cancer cell lines enhances DNA damage, impairs DNA repair, alters chromatin accessibility, and activates the cGAS-STING pathway. ARID1B deficiency is associated with immune suppression, indicated by reduced immune scores, decreased immune cell infiltration, and negative correlations with immune-related cell types and functions.

Conclusion: ARID1B mutation may predict improved response to ICIs in NSCLC patients. ARID1B mutation leads to impaired DNA damage response and repair, altered chromatin accessibility, and cGAS-STING pathway activation. These findings provide insights into ARID1B's biology and therapeutic implications in lung cancer, highlighting its potential as a target for precision medicine and immunotherapy. Further validation and clinical studies are warranted.

Keywords: ARID1B mutation, NSCLC, ICIs, cGAS-STING pathway, Chromatin Accessibility, DNA Damage

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APA

Zhu, G., Liu, J., Li, Y., Huang, H., Chen, C., Wu, D., Cao, P., Su, L., Wang, Y., Zhang, H., Liu, H., Chen, J. (2024). ARID1B Deficiency Leads to Impaired DNA Damage Response and Activated cGAS-STING Pathway in Non-Small Cell Lung Cancer. Journal of Cancer, 15(9), 2601-2612. https://doi.org/10.7150/jca.91955.

ACS

Zhu, G.; Liu, J.; Li, Y.; Huang, H.; Chen, C.; Wu, D.; Cao, P.; Su, L.; Wang, Y.; Zhang, H.; Liu, H.; Chen, J. ARID1B Deficiency Leads to Impaired DNA Damage Response and Activated cGAS-STING Pathway in Non-Small Cell Lung Cancer. J. Cancer 2024, 15 (9), 2601-2612. DOI: 10.7150/jca.91955.

NLM

CSE

Zhu G, Liu J, Li Y, Huang H, Chen C, Wu D, Cao P, Su L, Wang Y, Zhang H, Liu H, Chen J. 2024. ARID1B Deficiency Leads to Impaired DNA Damage Response and Activated cGAS-STING Pathway in Non-Small Cell Lung Cancer. J Cancer. 15(9):2601-2612.

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