{"title":"Targeting ATM enhances radiation sensitivity of colorectal cancer by Potentiating radiation-induced cell death and antitumor immunity","authors":"Yuwen Xie, Yang Liu, Mingdao Lin, Zhenkang Li, Zhiyong Shen, Shengqi Yin, Yilin Zheng, Yishu Zou, Yaowei Zhang, Yizhi Zhan, Yuan Fang, Yi Ding","doi":"10.1016/j.jare.2024.12.023","DOIUrl":null,"url":null,"abstract":"<h3>Introduction</h3>The efficacy of radiotherapy in colorectal cancer (CRC) is often limited by radiation resistance. Ataxia telangiectasia mutated (ATM) is well known for its role in repairing double-strand DNA breaks within the DNA damage response (DDR) pathway. However, whether ATM mediates other mechanisms contributing to radiation resistance remains insufficiently investigated.<h3>Objectives</h3>This study investigates how targeting ATM enhances CRC radiation sensitivity and evaluates combination strategies to improve radiotherapy outcomes.<h3>Methods</h3>Clinical specimens were analyzed to correlate ATM activation with radiotherapy response. Functional assays, including EdU, cell viability, clonogenic survival, and apoptosis assays, were used to assess the impact of ATM inhibition on radiation sensitivity. Mechanistic insights were gained through RNA-seq, RT-qPCR, western blotting, ELISA, immunofluorescence, flow cytometry, ChIP-qPCR, and co-immunoprecipitation. In vivo efficacy was evaluated using subcutaneous tumor models in nude, BALB/c, and C57BL/6J mice.<h3>Results</h3>High ATM phosphorylation levels correlated with poor radiotherapy response in CRC patients. ATM inhibition enhanced radiation sensitivity in both in vitro and in vivo models. Mechanistically, ATM inhibition increased radiation-induced ROS accumulation and mitochondrial damage, leading to the release of mitochondrial DNA (mtDNA) into the cytosol and activation of the STING-type I interferon pathway. This enhanced CD8+ T cell infiltration and boosted antitumor immunity. Additionally, ATM inhibition partially alleviated the radiation-induced upregulation of PD-L1, likely through the ATM/NEMO/NF-κB pathway. Notably, triple therapy combining radiotherapy, an ATM inhibitor, and anti-PD-L1 achieved superior tumor control and remission in mouse models, including large, treatment-resistant tumors.<h3>Conclusion</h3>Targeting ATM enhances radiation-induced tumor cell death and boosts antitumor immune responses, offering a promising strategy to overcome CRC radiation resistance. The synergy of radiotherapy, ATM inhibitior, and immune checkpoint blockade highlights a novel therapeutic approach for CRC management.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"96 1","pages":""},"PeriodicalIF":11.4000,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Advanced Research","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1016/j.jare.2024.12.023","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction
The efficacy of radiotherapy in colorectal cancer (CRC) is often limited by radiation resistance. Ataxia telangiectasia mutated (ATM) is well known for its role in repairing double-strand DNA breaks within the DNA damage response (DDR) pathway. However, whether ATM mediates other mechanisms contributing to radiation resistance remains insufficiently investigated.
Objectives
This study investigates how targeting ATM enhances CRC radiation sensitivity and evaluates combination strategies to improve radiotherapy outcomes.
Methods
Clinical specimens were analyzed to correlate ATM activation with radiotherapy response. Functional assays, including EdU, cell viability, clonogenic survival, and apoptosis assays, were used to assess the impact of ATM inhibition on radiation sensitivity. Mechanistic insights were gained through RNA-seq, RT-qPCR, western blotting, ELISA, immunofluorescence, flow cytometry, ChIP-qPCR, and co-immunoprecipitation. In vivo efficacy was evaluated using subcutaneous tumor models in nude, BALB/c, and C57BL/6J mice.
Results
High ATM phosphorylation levels correlated with poor radiotherapy response in CRC patients. ATM inhibition enhanced radiation sensitivity in both in vitro and in vivo models. Mechanistically, ATM inhibition increased radiation-induced ROS accumulation and mitochondrial damage, leading to the release of mitochondrial DNA (mtDNA) into the cytosol and activation of the STING-type I interferon pathway. This enhanced CD8+ T cell infiltration and boosted antitumor immunity. Additionally, ATM inhibition partially alleviated the radiation-induced upregulation of PD-L1, likely through the ATM/NEMO/NF-κB pathway. Notably, triple therapy combining radiotherapy, an ATM inhibitor, and anti-PD-L1 achieved superior tumor control and remission in mouse models, including large, treatment-resistant tumors.
Conclusion
Targeting ATM enhances radiation-induced tumor cell death and boosts antitumor immune responses, offering a promising strategy to overcome CRC radiation resistance. The synergy of radiotherapy, ATM inhibitior, and immune checkpoint blockade highlights a novel therapeutic approach for CRC management.
期刊介绍:
Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences.
The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.