BRD9 inhibition overcomes oncolytic virus therapy resistance in glioblastoma.

IF 10.6 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-08-19 Epub Date: 2025-07-30 DOI:10.1016/j.xcrm.2025.102258

Chen Guo, Zhilin Long, Peng Lin, Yinan Shen, Yiye Zhong, Jingjing Qian, Jichuan Yu, Weixi Zhao, Fuyi Liu, Yiling Ma, Jian Zheng, Jiayao Yang, Shuai Zhao, Xiaojuan Ran, Zhen Xia, Congying Wu, Yujia Cai, Chen Wang, Qi Xie

{"title":"BRD9 inhibition overcomes oncolytic virus therapy resistance in glioblastoma.","authors":"Chen Guo, Zhilin Long, Peng Lin, Yinan Shen, Yiye Zhong, Jingjing Qian, Jichuan Yu, Weixi Zhao, Fuyi Liu, Yiling Ma, Jian Zheng, Jiayao Yang, Shuai Zhao, Xiaojuan Ran, Zhen Xia, Congying Wu, Yujia Cai, Chen Wang, Qi Xie","doi":"10.1016/j.xcrm.2025.102258","DOIUrl":null,"url":null,"abstract":"<p><p>Long-term survival of glioblastoma multiforme (GBM) remains challenging, spurring the development of novel therapies such as oncolytic virus therapy. While oncolytic virus shows promise in clinical trials, many patients do not respond to this therapy. Here, we perform a CRISPR screening and identify the non-canonical BRG1/BRM-associated factor (ncBAF) complex as a pivotal tumor-intrinsic factor for oncolytic virotherapy resistance. Knocking out the ncBAF-specific subunit bromodomain-containing protein 9 (BRD9) markedly augments the oncolytic efficacy of oncolytic herpes simplex virus type 1 (oHSV1) and enhances antitumor immunity. Mechanistically, BRD9 binds to RELA and potentiates the expression of downstream antiviral genes. Notably, the application of BRD9 inhibitor (IBRD9) significantly enhances the oncolytic activity of oHSV1 in various GBM models. Moreover, reduced BRD9 levels strongly correlate with improved outcomes in clinical trials of oHSV1. These findings suggest that BRD9 is an attractive target for overcoming the resistance to oHSV1 in glioblastoma treatment.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102258"},"PeriodicalIF":10.6000,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432354/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Reports Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.xcrm.2025.102258","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/30 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Long-term survival of glioblastoma multiforme (GBM) remains challenging, spurring the development of novel therapies such as oncolytic virus therapy. While oncolytic virus shows promise in clinical trials, many patients do not respond to this therapy. Here, we perform a CRISPR screening and identify the non-canonical BRG1/BRM-associated factor (ncBAF) complex as a pivotal tumor-intrinsic factor for oncolytic virotherapy resistance. Knocking out the ncBAF-specific subunit bromodomain-containing protein 9 (BRD9) markedly augments the oncolytic efficacy of oncolytic herpes simplex virus type 1 (oHSV1) and enhances antitumor immunity. Mechanistically, BRD9 binds to RELA and potentiates the expression of downstream antiviral genes. Notably, the application of BRD9 inhibitor (IBRD9) significantly enhances the oncolytic activity of oHSV1 in various GBM models. Moreover, reduced BRD9 levels strongly correlate with improved outcomes in clinical trials of oHSV1. These findings suggest that BRD9 is an attractive target for overcoming the resistance to oHSV1 in glioblastoma treatment.

查看原文本刊更多论文

BRD9抑制克服了胶质母细胞瘤溶瘤病毒治疗的耐药性。

多形性胶质母细胞瘤（GBM）的长期生存仍然具有挑战性，这刺激了溶瘤病毒治疗等新疗法的发展。虽然溶瘤病毒在临床试验中显示出希望，但许多患者对这种治疗没有反应。在这里，我们进行了CRISPR筛选，并确定了非典型BRG1/ brm相关因子（ncBAF）复合物作为溶瘤病毒治疗耐药的关键肿瘤内在因子。敲除ncaff特异性含溴结构域蛋白9 （BRD9）可显著增强溶瘤性单纯疱疹病毒1型（oHSV1）的溶瘤效果，增强抗肿瘤免疫。从机制上讲，BRD9与RELA结合并增强下游抗病毒基因的表达。值得注意的是，BRD9抑制剂（IBRD9）的应用显著增强了oHSV1在各种GBM模型中的溶瘤活性。此外，BRD9水平的降低与oHSV1临床试验结果的改善密切相关。这些发现表明BRD9是胶质母细胞瘤治疗中克服oHSV1耐药性的一个有吸引力的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.