biostudies-literatureWatanabe JPediatric Cancer Research FoundationRally FoundationMatthew Larson Foundation for Pediatric Brain TumorsCure Starts Now FoundationNCI NIH HHSNINDS NIH HHSNational Institutes of HealthJapan Society for the Promotion of Sciencee174794https://www.ebi.ac.uk/biostudies/studies/S-EPMC11213469biostudies-literatureUnknown134(13)Diffuse midline glioma (DMG) H3K27-altered is one of the most malignant childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation antitumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair The Journal of clinical investigationBET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma.PMC11213469P50 CA221747N/A22IC36R01 NS126513R01CA1973135P50CA221747R01NS126513R01 CA277605R01 CA258636R01CA258636R01 CA197313R01 CA204297R01 NS093079863193R01 NS132344R01NS132344Gadd SClutter MRNatsumeda MSasaki TUchida EAbe KKaur SIshi YWatanabe JZhang ZBecher OJGullette MJTakata NMo YHashizume RfalseBET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma.Diffuse midline glioma (DMG) H3K27-altered is one of the most malignant childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation antitumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair 2024-01-01T00:00:00Z2024 May2026-07-15T12:00:49.401Z2026-07-04T03:12:02.63ZS-EPMC112134693877165510.1172/JCI174794