Pathway dysregulation and therapeutic resistance in glioblastoma: molecular mechanisms and emerging therapeutic targets

Abstract

Abstract Background: Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain tumor in adults and remains associated with poor survival despite advances in surgery, radiotherapy, and chemotherapy. Increasing evidence suggests that IDH-wildtype glioblastoma progression is driven by complex interactions between dysregulated molecular signaling pathways, intratumoral heterogeneity, glioma stem cells, and immune suppression within the tumor microenvironment. Objective: This narrative review summarizes the major signaling pathways implicated in GBM pathogenesis, including EGFR, PI3K/AKT/mTOR, Wnt, and TGF-β signaling, while also discussing emerging therapeutic targets such as FGFR3–TACC3 fusions, regorafenib, and natural killer cell-based immunotherapy. Results The review further examines mechanisms underlying treatment resistance and the limitations of current targeted therapies. Although many pathway-directed treatments have demonstrated promising preclinical activity, clinical translation remains challenging because of compensatory signaling, blood–brain barrier limitations, and molecular heterogeneity. Conclusion: Future progress will likely depend on biomarker-driven patient stratification, improved CNS drug delivery, and rational combination therapies capable of simultaneously targeting multiple tumor-promoting mechanisms.