Abstract 1831: Development and characterization of a radiation resistant GBM cell line from PDX for the screening of novel treatment modalities

Glioblastoma (GBM) remains one of the most lethal brain tumors, with standard-of-care therapies such as radiation and temozolomide offering limited survival benefit. Patient-derived xenograft (PDX) models have become critical tools for studying treatment resistance and identifying novel therapeutic strategies. Here, we report the establishment and characterization of a novel GBM cell line, ST146c, derived from a radiation-resistant PDX model (ST146). This cell line retains the therapy-resistant phenotype observed in the patient, making it a valuable resource for preclinical studies. To uncover vulnerabilities, ST146c was subjected to a mid-throughput drug screen, identifying SIK as a promising target. Subsequent in vitro studies confirmed that SIK inhibition significantly impairs ST146c cell proliferation and survival. To validate these findings, we conducted in vivo experiments using the parental PDX model. SIK inhibition demonstrated robust anti-tumor activity, corroborating the in vitro results and underscoring its potential as a therapeutic target in radiation-resistant GBM. Building upon these findings, we performed a focused synergy screen, testing 40 handpicked drugs in combination with radiation. Among these, SIK3 inhibition emerged as a top candidate, showing evidence of synergistic effects with radiation in vitro. We are now extending these investigations to in vivo models to further evaluate the potential for SIK3 inhibitors to enhance the efficacy of radiation therapy. This study highlights the translational potential of the ST146c model for identifying and validating novel therapies targeting radiation-resistant GBM. The discovery of SIK3 as both a monotherapy target and a radiation-sensitizing agent opens new avenues for overcoming resistance in this challenging disease. Citation Format: Sigrid Cold, Jérémy Ariey-Bonnet, Monica Brandt, Rikke Nørgaard Bøge, Emma Papin, Ida Thorøe Michler, Lotte Kellemann Kristensen, Jacob Hald, Michael Wick, Andreas Kjær, Krister Wennerberg, Carsten Hagen Nielsen, Sebastian Gnosa. Development and characterization of a radiation resistant GBM cell line from PDX for the screening of novel treatment modalities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1831.