Selek, U. | Search bioRxiv

bioRxiv2026

BRD9 inhibition induces selective radiosensitivity in glioblastoma through MYC pathway modulation

Radiotherapy (RT) is a cornerstone of glioblastoma (GBM) treatment, yet therapeutic resistance remains nearly universal due to the rapid activation of stress-adaptive survival programs. Identifying molecular regulators that sustain these adaptive responses may reveal context-dependent vulnerabilities that can be therapeutically exploited. Here, we performed an epigenetic drug screen under low-dose irradiation to identify modifiers of radiotherapy response in glioblastoma. We identify BRD9 inhibition as a priming strategy that selectively enhances irradiation-induced lethality without inducing substantial cytotoxicity under baseline conditions. Mechanistically, BRD9 perturbation delays the resolution of irradiation-induced DNA damage, leading to increased apoptosis following irradiation. This effect is selective for malignant glioblastoma cell lines and patient-derived primary cells, while sparing non-malignant human astrocytes. Transcriptomic profiling reveals that BRD9 inhibition or genetic depletion produces a coordinated, MYC-centered suppression of translational programs, including ribosome biogenesis, rRNA processing, tRNA aminoacylation, and translational initiation. Ectopic MYC expression attenuates BRD9-dependent radiosensitization, functionally linking MYC suppression to the enhanced radiation response. Importantly, analysis of independent glioblastoma patient cohorts reveals a consistent positive association between BRD9 and MYC expression, alongside elevated BRD9 expression in recurrent compared with primary tumors. Together, these findings identify BRD9 as a regulator of MYC-associated translational programs and support its therapeutic targeting as a strategy to enhance radiotherapy efficacy in glioblastoma.

cancer biology↗

bioRxiv2022

Chronically radiation-exposed survivor glioblastoma cells display poor response to Chk1 inhibition

Glioblastoma is the most common type of primary brain tumor with an aggressive clinical course, and one of the cornerstones in its treatment regimen is radiotherapy. However, tumor cells surviving after radiation is an indicator of treatment failure; therefore, better understanding of the molecular mechanisms regulating radiotherapy response is of utmost importance. In this study, we generated multiple clinically relevant irradiation exposed models, where we applied fractionated radiotherapy over a long period of time and selected irradiation-survivor (IR-Surv) glioblastoma cell populations. In these cells, we examined the transcriptomic alterations, cell cycle and growth rate changes as well as responses to secondary radiotherapy and DNA damage response (DDR) modulators. Accordingly, IR-Surv cells exhibited slower growth and partly retained their ability to resist secondary irradiation. Transcriptomic analysis revealed that IR-Surv cells upregulated the expression of DDR-related genes, such as CHK1, ATM, ATR, MGMT, and had better DNA repair capacity as an adaptive mechanism. Separately, we report IR-Surv cells to display downregulation of hypoxic signature and the lower induction of hypoxia target genes and not exhibiting the same level of hypoxia-induced changes with naive glioblastoma cells, as gauged by exposing cells to different hypoxia conditions. We also showed that Chk1 inhibition alone or in combination with irradiation significantly reduces cell viability in both naive and IR-Surv cells. However, IR-Surv cells were markedly less sensitive to Chk1 inhibition under hypoxic conditions. In conclusion, consistent with previous reports, we demonstrate the utility of combining DDR inhibitors and irradiation as a successful approach for both naive and IR-Surv glioblastoma cells as long as cells are refrained from hypoxic conditions. Thus, our findings with clinically relevant radiation survivor models will have future translational implications and benefit the optimization of combination therapies for glioblastoma patients.

cancer biology↗