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BRD9 inhibition overcomes oncolytic virus therapy resistance in glioblastoma

Chen Guo1, Zhilin Long2, Peng Lin3

  • 1College 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.

Cell Reports. Medicine
|July 31, 2025
PubMed

Insights

Researchers identified bromodomain-containing protein 9 (BRD9) as a key factor in glioblastoma resistance to oncolytic virus therapy. Inhibiting BRD9 enhances treatment efficacy and antitumor immunity, offering a new therapeutic target.

Area of Science:

  • Oncology
  • Virology
  • Genetics

Background:

  • Glioblastoma multiforme (GBM) presents significant challenges for long-term patient survival.
  • Oncolytic virus therapy shows promise but faces resistance in many patients.
  • Identifying tumor-intrinsic resistance factors is crucial for improving therapy outcomes.

Purpose of the Study:

  • To identify genetic factors contributing to resistance against oncolytic virotherapy in glioblastoma.
  • To investigate the role of the non-canonical BRG1/BRM-associated factor (ncBAF) complex in therapy resistance.
  • To evaluate bromodomain-containing protein 9 (BRD9) as a potential therapeutic target.

Main Methods:

  • Conducted CRISPR screening to identify genes involved in oncolytic virotherapy resistance.
  • Utilized oncolytic herpes simplex virus type 1 (oHSV1) in glioblastoma models.
  • Assessed the impact of BRD9 knockout and inhibition on oHSV1 efficacy and antitumor immunity.
  • Analyzed the molecular mechanism of BRD9's role in antiviral gene expression.

Main Results:

  • The ncBAF complex, specifically BRD9, was identified as a critical factor in oncolytic virotherapy resistance.
  • Knocking out BRD9 significantly enhanced the efficacy of oHSV1 and boosted antitumor immunity.
  • BRD9 inhibition with IBRD9 improved oHSV1 activity in various GBM models.
  • BRD9 was found to bind RELA, enhancing the expression of antiviral genes.

Conclusions:

  • BRD9 is a pivotal tumor-intrinsic factor driving resistance to oHSV1 in glioblastoma.
  • Targeting BRD9 presents a promising strategy to overcome oncolytic virotherapy resistance.
  • Reduced BRD9 levels correlate with better outcomes in clinical trials, supporting its role as a therapeutic target.
Keywords:
glioblastomaoncolytic virustherapy resistance

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