Ion channel modulator DPI-201-106 significantly enhances antitumor activity of DNA damage response inhibitors in glioblastoma
Background: Glioblastoma, a highly aggressive and lethal form of high-grade glioma, has seen little to no improvement in clinical outcomes over the past three decades. Ion channels are increasingly recognized as contributors to tumorigenesis, and numerous brain-penetrant ion channel inhibitors are available, offering a largely unexplored therapeutic avenue. This exploratory study aimed to screen a library of ion channel-targeting drugs against patient-derived glioblastoma cells to identify novel treatment options for this devastating disease.
Methods: A library of 72 ion channel inhibitors was screened for effects on patient-derived glioblastoma cell viability using the ViaLight Assay. Cell cycle progression and apoptosis were assessed via flow cytometry with propidium iodide (PI) and Annexin V staining, respectively. Protein and phosphoprotein expression changes were analyzed through LY2606368 mass spectrometry, followed by gene set enrichment analysis. Survival outcomes were evaluated using Kaplan-Meier analyses in intracranial xenograft models of GBM6 and WK1 glioblastoma cells.
Results: The voltage-gated sodium channel modulator DPI-201-106 significantly reduced glioblastoma cell viability in vitro by inducing cell cycle arrest and apoptosis. Phosphoproteomic analysis suggested that DPI-201-106 disrupts DNA damage response (DDR) pathways. Moreover, combining DPI-201-106 with the CHK1 inhibitor prexasertib or the PARP inhibitor niraparib produced synergistic effects in multiple patient-derived glioblastoma models in vitro and in intracranial xenograft mouse models. This combination therapy notably extended survival in glioblastoma-bearing mice.
Conclusions: DPI-201-106 enhances the therapeutic efficacy of DDR inhibitors in reducing glioblastoma growth. Given that these drugs have already undergone clinical testing, repurposing DPI-201-106 in combination with DDR-targeting agents offers a promising strategy for rapid clinical translation to improve outcomes for glioblastoma patients.