Radiotherapy is used for treatment of pediatric brain tumors including medulloblastoma, ependymoma and diffused midline glioma. We have demonstrated that the epigenetic mark H3K27me3 is lost in half of group 3 and 4 medulloblastoma patients resulting in radiation resistance and worse clinical outcomes. Mechanistically, loss of H3K27me3 drives an increase in H3K27ac leading to an enhanced expression of EPHA2 that triggers excessive pro-survival AKT signaling after radiation. Suppressing H3K27ac levels by BET restores radiation sensitivity in H3K27me3-deficient medulloblastoma, thus establishing a novel epigenetically guided treatment approach. Notably, loss of H3K27me3 is characteristic for diffused midline glioma and PFA group ependymoma suggesting that combination of radiation with BET inhibitors may improve outcomes in these tumors as well. Together, we propose targeting H3K27me3-deficient brain tumors with BET inhibitors to improve radiation response.

To be updated.