CSIG-27. GLIOBLASTOMA CELL STATE PLASTICITY AND THERAPEUTIC RESISTANCE IS MEDIATED BY BRD2

Abstract GBM is a highly aggressive primary brain tumor in adults, notable for its heterogeneity, high recurrence rates, and increased resistance to therapy. Multi-omics analyses have consistently identified three distinct transcriptionally defined cell states – proneural (PN), classical (CL), and mesenchymal (MES) – in IDH-wildtype GBM, with high plasticity among these states in response to diverse stimuli. Transition of GBM cells to a MES cell state is particularly associated with high invasiveness, resistance to therapy, and recurrence. However, the underlying mechanisms driving the MES transition remain poorly understood. In this study we identified the PTEN/NF-kB/BRD2 pathway as key driver of the MES transition, with BRD2 acting as a crucial epigenetic modulator for cell state transitions in GBM. We demonstrate that PTEN plays a critical role in regulating the chromatin binding of BRD2, BRD4 and p65/RelA. Additionally, acetylation of RelA at lysine 310 is required for BRD2 localization to the promoters of MES genes, which is essential for their expression. Loss of BRD2 leads to transition of GBM cells from MES to PN cell state and displayed enhanced sensitivity to ionizing radiation (IR). Further, bromo domains (BDs) of BRD2 are important for MES transition, as mutations in these domains resulted in transitioning of GBM cells from MES to other cell states. Furthermore, we show that BD2-specific BET inhibitors displace BRD2 from MES gene promoters, abrogate MES transition, and enhance GBM sensitivity to IR. Using a brain-penetrant BD2 inhibitor, we effectively reduced GBM cell invasion and tumor-associated microglia/macrophage (TAM) abundance in orthotopic xenograft models. These findings establish BRD2 as a key regulator of MES transition and therapeutic resistance in GBM models, paving the way for the use of bromodomain-specific BET inhibitors in targeting MES GBM.