ATM and ATR inhibition increases radiosensitivity and cGAS-STING activation in prostate cancer

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine Pub Date : 2025-06-17 DOI:10.1016/j.cyto.2025.156980

Nina van Campen, Vera E. Mekers, Maaike W. Looman, Lune van den Bogaard, Esther D. Kers-Rebel, Wenny J.M. Peeters, Esther Fernández Merino, Fabian Schuurmans, Robert Jan Smeenk, Marcel Verheij, Marleen Ansems, Gosse J. Adema

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Abstract

Despite the availability of multiple effective therapies for localized prostate cancer, many patients still progress to incurable metastasized castration resistant prostate cancer (mCRPC). About 23 % of mCRPC patients carry alterations in DNA damage response (DDR) genes, including the protein kinases Ataxia telangiectasia mutated (ATM). DDR gene mutations have been shown to increase radiosensitivity and responses to immunotherapy. Here, we aimed to investigate the effect of inhibiting ATM and Ataxia telangiectasia and Rad3 related (ATR) on the radiosensitivity and subsequent activation of the cGAS-STING pathway in three prostate cancer cell lines. The data demonstrate that ATM and ATR inhibition leads to increased radiosensitivity in the PC3 and DU145 cell lines and that simultaneous inhibition of ATM and ATR results in enhanced cell death after irradiation. Furthermore, ATM blockade or combined ATM and ATR inhibition, but not ATR inhibition alone, significantly enhances radiation-induced cGAMP levels and a gene expression signature induced by the cytokine type I interferon. This work highlights the promising effects of ATM and ATR inhibition in combination with radiotherapy in prostate cancer and offers opportunities for exploring the use of radiotherapy and immunotherapy combinations in mCRPC.

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ATM和ATR抑制增加前列腺癌的放射敏感性和cGAS-STING激活

尽管有多种有效的治疗方法可用于局部前列腺癌，但许多患者仍进展为无法治愈的转移性去势抵抗性前列腺癌（mCRPC）。大约23%的mCRPC患者携带DNA损伤反应（DDR）基因的改变，包括蛋白激酶共济失调毛细血管扩张突变（ATM）。DDR基因突变已被证明可增加放射敏感性和对免疫治疗的反应。在这里，我们旨在研究抑制ATM和Ataxia毛细血管扩张和Rad3相关（ATR）对三种前列腺癌细胞系cGAS-STING通路放射敏感性和随后激活的影响。数据表明，ATM和ATR抑制导致PC3和DU145细胞系的放射敏感性增加，同时抑制ATM和ATR导致辐照后细胞死亡增加。此外，ATM阻断或ATM和ATR联合抑制，而不是ATR单独抑制，显著提高辐射诱导的cGAMP水平和细胞因子I型干扰素诱导的基因表达特征。这项工作强调了ATM和ATR抑制联合放疗治疗前列腺癌的前景，并为探索放疗和免疫治疗联合治疗mCRPC提供了机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cytokine 医学-免疫学

CiteScore

7.60

自引率

2.60%

发文量

262

审稿时长

48 days

期刊介绍： The journal Cytokine has an open access mirror journal Cytokine: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. * Devoted exclusively to the study of the molecular biology, genetics, biochemistry, immunology, genome-wide association studies, pathobiology, diagnostic and clinical applications of all known interleukins, hematopoietic factors, growth factors, cytotoxins, interferons, new cytokines, and chemokines, Cytokine provides comprehensive coverage of cytokines and their mechanisms of actions, 12 times a year by publishing original high quality refereed scientific papers from prominent investigators in both the academic and industrial sectors. We will publish 3 major types of manuscripts: 1) Original manuscripts describing research results. 2) Basic and clinical reviews describing cytokine actions and regulation. 3) Short commentaries/perspectives on recently published aspects of cytokines, pathogenesis and clinical results.