Abstract 4697: FDA approved non-cardiotoxic hERG1 inhibitor ketoconazole enhances radiation sensitivity in glioblastoma

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a median survival of less than two years despite multimodal therapy, including surgery, radiation, chemotherapy, and tumor treating fields. GBM's dismal prognosis is largely due to its high recurrence rates. Emerging evidence implicates ion channels in promoting tumor progression and treatment resistance across various malignancies. Specifically, the potassium voltage-gated channel hERG1, encoded by the KCNH2 gene, has been associated with worse patient outcomes in GBM. However, the mechanisms underlying hERG1’s contribution to treatment resistance, particularly radiation resistance, remain poorly understood. Here, we investigated the role of hERG1 in driving radiation resistance in GBM. RNA-sequencing data from 350 GBM patient tumors in The Cancer Genome Atlas (TCGA) were analyzed to assess KCNH2 expression and its correlation with overall survival. Patients were stratified into quartiles by KCNH2 expression, and Kaplan-Meier survival analyses were performed using R Studio (v4.3.1). The human GBM cell line LN-229 was used for in vitro studies. A drug screen determined the IC25 for an FDA-approved, non-cardiotoxic hERG1 inhibitor ketoconazole. Cell viability was assessed after 72 hours of drug treatment. Cells were treated with IC25 concentrations of inhibitors for three days, with radiation (0 Gy or 8 Gy) administered on day two, followed by two additional days of drug treatment. All experiments were performed in triplicate for statistical rigor. KCNH2 expression in the upper quartile was 9.7 times higher than in the lower quartile. Patients in the upper quartile exhibited worse median overall survival compared to those in the lower quartile (11.8 months vs. 12.9 months, p = 0.00053). The IC25 for ketoconazole was 28μM. Ketoconazole combined with radiation decreased cell viability by 54.4% compared to radiation alone (p =0.01) and by 78.8% compared to vehicle control (p < 0.0001). High KCNH2 expression is associated with worse survival outcomes in GBM patients. FDA-approved, non-cardiotoxic hERG1 inhibitor ketoconazole decreased cell viability and enhanced radiation sensitivity in vitro. These findings suggest that combining a non-cardiotoxic hERG1 inhibitor with radiation may represent a promising therapeutic strategy to improve GBM patient outcomes. Citation Format: Johnathan Rodgers Gochicoa, Tingting Huang, Kelli B. Pointer. FDA approved non-cardiotoxic hERG1 inhibitor ketoconazole enhances radiation sensitivity in glioblastoma [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 4697.