EXTH-08. BRD2 bromodomain-mediated regulation of cell state plasticity modulates therapy response in glioblastoma

Glioblastoma (GBM) exhibits extensive cell state plasticity that constitutes a primary mechanism of therapeutic resistance and disease progression. Despite recognition that epigenetic regulators drive this plasticity, the critical molecular mediators remain inadequately characterized, limiting the development of targeted therapeutic interventions. This study employed GBM patient-derived xenograft cell lines, CRISPR-mediated genetic modification, RNA sequencing, and comprehensive in vitro and in vivo modeling to elucidate the role of BRD2 in regulating NF-κB-mediated mesenchymal transition. Our investigation revealed that PTEN loss induces RelA chromatin localization and acetylation, subsequently recruiting BRD2 to mesenchymal gene promoters where it functions as an essential regulator of gene expression and phenotype maintenance. Genetic deletion or pharmacological inhibition of BRD2 bromodomains effectively reversed mesenchymal transition, enhanced radiation sensitivity, and significantly improved survival outcomes in preclinical models. Treatment with a brain-penetrant BD2-selective inhibitor demonstrated suppression of mesenchymal gene expression, increased radiosensitivity of glioblastoma stem cells, reduced invasion capacity, and decreased tumor-associated macrophage infiltration in vivo. These findings establish BRD2 as a central mediator of mesenchymal transition in GBM, with its bromodomains serving as critical drivers of cell state plasticity through chromatin regulation. The therapeutic targeting of BRD2 with BD2-selective inhibitors represents a promising strategy to overcome treatment resistance and improve patient outcomes. This work provides mechanistic insight into the epigenetic control of GBM plasticity and identifies a clinically actionable target for combination with standard therapeutic approaches.