Interrogating the Role of Chromatin Regulator BRD4 in the DNA Damage Response in Medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC-driven tumors make up 40% of MBs and display the poorest prognosis. Treatment often has debilitating effects on patients, thus, novel molecularly targeted therapies could minimize adverse effects and improve treatment. Bromodomain and Extra-terminal domain (BET) inhibitors were introduced as an alternative strategy for targeting MYC proteins, by impairing epigenetic regulation of MYC transcription. Emerging data show that MYC repression is not the only effect that BET inhibition has on various cancers. We interrogated the role of chromatin regulator BRD4 in the DNA damage response in MB. We showed that small-molecule BET inhibition can down-regulate key DNA repair proteins of various DNA repair pathways, and that BET inhibitors and BET degraders synergize with other established chemotherapeutic compounds in MB cell lines. We further demonstrated that transcriptional repression results in defective DNA repair, suggesting that the development of drug-combination therapies including BET-inhibitors and established first-line MB agents may enhance drug efficacy in MB patients.