EMBR-04. BET INHIBITION TARGETS RADIOTHERAPY RESISTANCE IN H3K27ME3-DEFICIENT GROUP 3 MEDULLOBLASTOMA

Abstract

\n Medulloblastoma has been categorized into four subgroups based on genetic, epigenetic and transcriptional profiling. However, molecular pathways determining radiotherapy response in this tumor remain elusive. Here, we investigated the role of the EZH2-dependent histone H3K27 tri-methylation in radiotherapy response in medulloblastoma. We demonstrate that 47.2% of group 3 and 4 medulloblastoma patients have H3K27me3-deficient tumors. Loss of H3K27me3 was associated with a radioresistant phenotype, high relapse rates and poor overall survival. We show that an epigenetic switch from H3K27me3 to H3K27ac occurs at specific genomic loci in H3K27me3-deficient medulloblastoma cells altering the transcriptional profile. The resulting up-regulation of EPHA2 (ephrin type-A receptor 2) stimulates an excessive activation of the pro-survival AKT signaling pathway leading to radiotherapy resistance. We show that BET inhibition targets radiation resistance in H3K27me3-deficient medulloblastoma by suppressing H3K27ac levels, blunting EPHA2 overexpression and mitigating the excessive AKT signaling. Additionally, BET inhibition sensitizes medulloblastoma cells to radiation by enhancing apoptotic response through suppression of Bcl-XL and up-regulation of Bim expression. Our work demonstrates a novel mechanism of radiation resistance in medulloblastoma and identifies an epigenetic marker predictive of radiotherapy response. Based on these findings we propose an epigenetically guided treatment approach targeting radiotherapy resistance in medulloblastoma patients.