BRD2 Bromodomain-Mediated Regulation of Cell State Plasticity Modulates Therapy Response in Glioblastoma.

Abstract

Background: Glioblastoma (GBM) displays remarkable cell state plasticity, a major contributor to therapeutic resistance and tumor progression. While epigenetic mechanisms play a central role in driving this plasticity, the key regulators remain poorly understood, and developing effective therapeutic strategies targeting them has been challenging.

Methods: We investigated the role of BRD2, a key regulator of NF-κB mediated mesenchymal (MES) transition, using GBM patient-derived xenograft (PDX) cell lines, CRISPR-mediated knock-in/knockout approaches, RNA-seq, and in vitro and in vivo modeling. BET inhibitors were employed to target MES gene expression and sensitize GBM to radiation therapy.

Results: We found that PTEN loss induces RelA chromatin localization and acetylation-mediated recruitment of BRD2 to the MES gene promoters. BRD2 binding is essential for maintaining MES gene expression and phenotype. Genetic ablation or loss-of-function mutation of BRD2 bromodomains reverses MES transition, enhances radiation sensitivity, and improves survival in orthotopic xenograft models. Additionally, treatment with a brain-penetrant BD2-selective inhibitor suppresses the MES phenotype and increases radiation sensitivity of GBM stem cells in vitro.

Conclusion: Our study identifies BRD2 as a key mediator of MES transition in GBM, with its bromodomains playing a crucial role in driving cell state plasticity. Targeting BRD2 with BD2-selective inhibitors offers a promising therapeutic strategy to overcome radiation resistance and improve outcomes for GBM patients.