S2638
Radiobiology - Tumour radiobiology
ESTRO 2026
Results: BRD9 inhibition significantly enhanced RT-induced cytotoxicity in GBM cells but not in non-malignant astrocytes, indicating a cancer cell-specific phenotype. Complementary to chemical inhibition, CRISPR/Cas9- based ablation of BRD9 also sensitized glioblastoma cells to ionizing radiation (IR). In parallel, long-term IR- exposed cell populations, as a model of IR-resistance, exhibited increased expression of BRD9 and low response to combined treatment with IR and BRD9 inhibitor. Transcriptomic profiling revealed downregulation of MYC-dependent translational and ribosomal biogenesis programs, accompanied by decreased global protein synthesis in BRD9-inhibited GBM cell lines. Importantly, ectopic MYC expression reversed the radiosensitizing phenotype, confirming MYC pathway suppression as the primary mediator of BRD9-dependent RT response. BRD9 targeting thus induces a transcriptionally and metabolically fragile state that increases GBM susceptibility to
Keywords: metabolomics HIF heterogeneity
radiotherapy. Conclusion:
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Taken together, our findings suggest a regulatory role for BRD9 in radiotherapy response, highlighting the potential of targeting BRD9 as a therapeutic approach for glioblastoma. BRD9 inhibition suppresses MYC- driven translation and creates a cancer-specific vulnerable state that enhances RT efficacy. This study provides new insights into the molecular mechanisms underlying the poor response to radiotherapy and identifies a potential avenue for improving treatment outcomes in glioblastoma patients. Keywords: glioblastoma, BRD9, radiosensitization A transcriptomic signature predicts radiation response in a heterogenous cohort of patient- derived organoids resembling oesophageal adenocarcinoma Gunjan Katyal 1,2 , Daniel Jacobson 3 , Victoria Askinyte 3 , Hannah Coles 3 , Ginny Devonshire 3 , Rebecca C Fitzgerald 3 , Christopher M Jones 1,3 1 CRUK RadNet Cambridge, University of Cambridge, Cambridge, United Kingdom. 2 CRUK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom. 3 Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom Proffered Paper 4197 Purpose/Objective: Therapeutic options for locally advanced oesophageal adenocarcinoma (OAC) are limited and less than 20% of patients respond adequately to chemoradiotherapy1. The biological determinants of this intrinsic radiation resistance are poorly understood, yet their characterisation is essential for
BRD9 inhibition induces selective radiosensitivity in glioblastoma through MYC pathway modulation Nareg Degirmenci 1 , Serdar Aksel Celikkol 1 , Beyza Nur Koseoglu 1 , Neelam Mehta 2 , Udo Oppermann 2 , Adam Cribbs 2 , Ugur Selek 3 , Tugba Bagci-Onder 1 1 Koç University Research Center for Translational Medicine, Koç University, Istanbul, Turkey. 2 Botnar Research Centre, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom. 3 School of Medicine, Koç University, Istanbul, Turkey Purpose/Objective: Radioresistance is a major cause of treatment failure in glioblastoma (GBM). To identify epigenetic targets that modulate radiotherapy (RT) response, we performed a chemical screen utilizing an epigenetic drug library targeting 120 chromatin modifiers. From this screen, BRD9 inhibitors emerged as potent radiosensitizers. In this study, we aimed to elucidate the molecular mechanism underlying BRD9-mediated RT resistance and its link to MYC-driven translational control. Material/Methods: An epigenetic chemical library screen was performed in combination with fractionated RT across established GBM cell lines. Radiosensitization was evaluated using clonogenic survival, γ H2AX foci formation, and apoptosis assays. RNA sequencing was performed following pharmacological inhbition or genetic ablation of BRD9. Functional rescue assays were conducted via lentiviral MYC overexpression to assess pathway dependency.
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