ESTRO 2025 - Abstract Book

S4027

Radiobiology - Tumour radiobiology

ESTRO 2025

4416

Digital Poster Inhibitors of the enzyme Arginine Methyltransferase (PRMT) are identified as radiosensitizers in glioblastoma cells through a chemical screen Beyza Nur Koseoglu 1,2 , Nareg Pınarbası-Degirmenci 1,2 , Melis Selek 1 , Altar Ozbıyık 1,2 , Ugur Selek 3 , Tugba Bagcı Onder 1,2 1 Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul, Turkey. 2 Research Center for Translational Medicine, Koç University, Istanbul, Turkey. 3 Department of Radiation Oncology, Koç University School of Medicine, Istanbul, Turkey Purpose/Objective: Radiotherapy (RT) is a cornerstone of survival-prolonging treatment for glioblastoma (GBM), a largely incurable primary malignant brain tumor. The treatment failure relies on the adaptation of tumor cells to treatment and resistance, which is a major reason for inevitable recurrence. Understanding the molecular mechanisms behind this adaptive resistance and designing effective therapeutic strategies are of utmost priority. Therefore, finding epigenetic modulators of radiotherapy response, in other words, “radiosensitizers”, will be crucial for glioblastoma patients. Material/Methods: To investigate the epigenetic factors regulating glioblastoma cell survival, a chemical screen using 146 epigenetic drugs against chromatin modifiers, that involve inhibitors of the epigenetic writer and eraser enzymes, was conducted. From this screen, inhibitors of Arginine methyltransferase (PRMT) family were identified as radiosensitizers. PRMT inhibitors (MS023, MS049, SGC707, and LLY283) were tested on U373 and U87 GBM cell lines, and the optimal drug doses were determined through cell viability and colony formation assays. The combined effects of MS023, an inhibitor of PRMT1/6 methyltransferase activity, with radiation, were further investigated by analyzing the impact on the GBM cell transcriptome through RNA sequencing-based transcriptomic profiling. In addition to the chemical approach, CRISPR/Cas9-based genetic ablation was used to reduce the expression of genes encoding different PRMT family members. The combined effects of genetic ablation and radiation therapy (RT) were then examined to assess their potential synergistic impact on GBM cell survival. Results: The results of the chemical screen indicated that inhibition of PRMT significantly enhanced the response to radiation therapy (RT) in glioblastoma (GBM) cells. Notably, low doses of MS023 reduced cell survival and proliferation capacity when combined with RT. Transcriptomic profiling revealed that this combination therapy downregulated key pathways associated with DNA replication and the cell cycle. Furthermore, genetic ablation of PRMT1 and PRMT6—the primary targets of MS023—significantly impacted cell survival and reduced colony formation capacity in GBM cell lines when combined with radiation. To further test our findings, primary GBM cell lines were then used to assess the combination therapy, and the results aligned with earlier findings, emphasizing the enhanced synergistic effect of PRMT inhibition and RT, reinforcing its potential as a promising therapeutic strategy. Conclusion: These findings establish a foundational framework for identifying RT resistance mechanisms and devising innovative combination therapy strategies tailored for GBM. The observed effects of PRMT inhibition on RT response offer promising avenues for future research and potential clinical applications.

Keywords: Glioblastoma, Epigenetics, Radiosensitization