BRD9 inhibition overcomes oncolytic virus therapy resistance in glioblastoma

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

BRD9 inhibition overcomes oncolytic virus therapy resistance in glioblastoma

Cell Rep Med. 2025 Aug 19;6(8):102258. doi: 10.1016/j.xcrm.2025.102258. Epub 2025 Jul 30.

Authors

Chen Guo¹, Zhilin Long², Peng Lin³, Yinan Shen⁴, Yiye Zhong⁵, Jingjing Qian², Jichuan Yu², Weixi Zhao², Fuyi Liu⁶, Yiling Ma⁶, Jian Zheng⁶, Jiayao Yang², Shuai Zhao², Xiaojuan Ran², Zhen Xia², Congying Wu², Yujia Cai⁷, Chen Wang⁸, Qi Xie⁹

Affiliations

¹ College of Life Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310030, China; Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, China; School of Life Sciences, Westlake University, Hangzhou 310030, China.
² Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310030, China; Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, China; School of Life Sciences, Westlake University, Hangzhou 310030, China.
³ Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310030, China; Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, China; School of Life Sciences, Westlake University, Hangzhou 310030, China; National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China.
⁴ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, China.
⁵ Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
⁶ Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
⁷ Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China; State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: yujia.cai@sjtu.edu.cn.
⁸ National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China. Electronic address: wc@ism.pumc.edu.cn.
⁹ Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310030, China; Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, China; School of Life Sciences, Westlake University, Hangzhou 310030, China. Electronic address: xieqi@westlake.edu.cn.

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.

Keywords: glioblastoma; oncolytic virus; therapy resistance.

MeSH terms

Animals
Brain Neoplasms* / genetics
Brain Neoplasms* / therapy
Bromodomain Containing Proteins
Cell Line, Tumor
Glioblastoma* / genetics
Glioblastoma* / metabolism
Glioblastoma* / pathology
Glioblastoma* / therapy
Glioblastoma* / virology
Herpesvirus 1, Human
Humans
Mice
Mice, Nude
Oncolytic Virotherapy* / methods
Oncolytic Viruses* / physiology
Transcription Factor RelA / metabolism
Transcription Factors* / antagonists & inhibitors
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Transcription Factors
BRD9 protein, human
Transcription Factor RelA
RELA protein, human
Bromodomain Containing Proteins