Molecular Insights into Glioblastoma Resistance and Implications for Treatment Advancements: A Systematic Review

Glioblastoma (GBM) is a highly resistant brain tumor with a dismal prognosis despite standard treatments like temozolomide (TMZ) and radiation therapy (RT). This review delineates the molecular mechanisms driving this resistance to inform future therapeutic strategies. A narrative review was conducted using PubMed, synthesizing studies from the year 2000 up to March 2025 on DNA repair enzymes, TMZ and RT resistance pathways, anti-apoptosis mechanisms, genetic heterogeneity, and cell cycle dysregulation in GBM. Five key resistance mechanisms were identified: (1) DNA repair enzymes (e.g., MGMT, APNG) counteract TMZ-induced damage, regulated by NF-κB and CHD4; (2) TMZ and RT resistance depends on MGMT methylation and MMR functionality; (3) anti-apoptotic pathways (e.g., Bcl-2, PI3K/Akt) protect GBM cells, mitigated by TRAIL sensitization; (4) genetic mutations (EGFR, PTEN, TP53) confer adaptability; and (5) quiescent and proliferative GBM stem cells (GSCs) sustain recurrence. Novel therapies targeting HK2 and neural stem cells show promise. GBM resistance is multifaceted, requiring personalized, multi-targeted approaches. Future research should prioritize epigenetic modulation and combination therapies to enhance patient outcomes.