DIAPH3 Loss Enhances Chemoresistance in MGMT-Methylated Glioblastoma Cells Through FGFR2 Upregulation

Mitotic errors and aneuploidy cause genomic alterations and generate karyotypes that provide tumor cells with growth and survival advantages, enabling them to resist genotoxic insults. Glioblastoma (GBM) tumors are characterized by a high degree of aneuploidy, resistance to therapy, and frequent recurrence, emphasizing the need for additional targetable molecules that can circumvent resistance to standard-of-care strategies and advance therapy. In this paper, we identify DIAPH3 loss as a driver of resistance to Temozolomide (TMZ) and demonstrate its key role in survival of GBM cells. By depleting DIAPH3 expression, we describe how chromosomal instability drives an atypical DNA damage response (DDR) and adaptive mechanisms that collectively support TMZ resistance while blunting apoptosis and evading cell cycle checkpoints. Transcriptomic profiling of DIAPH3-deficient cells further revealed upregulation of Fibroblast Growth Factor Receptor 2 (FGFR2), previously linked to DNA repair and radioresistance in glioma, and whose knockdown significantly reduced cell survival under TMZ pressure, establishing FGFR2 as a driver of resistance to therapy in GBM cells. Our findings emphasize a mechanistic link between mitotic fidelity, chromosomal instability, and chemotherapy resistance and may have important clinical implications for understanding and treating glioblastoma. We identify DIAPH3 as a prognostic factor and promising therapeutic target specifically in GBM patients harboring a methylated MGMT promoter; the population most likely to benefit from TMZ treatment. Monitoring DIAPH3 and FGFR2 expression levels may help predict therapy resistance and improve the treatment outcome for MGMT-methylated glioblastoma patients.