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INTERNATIONAL CONGRESS OF

PharmacoGenetics

• MGMT Silencing and EGFR Amplification Synergy in Glioblastoma: Implications for Therapeutic Resistance

• Arman Taran,^1,* Mina Shirmohammadpour,² Bahman Mirzaei,³
  1. Zanjan University of Medical Sciences
  2. Zanjan University of Medical Sciences
  3. Zanjan University of Medical Sciences
  
  
  
• Introduction: Glioblastoma (GBM) represents the most aggressive primary brain tumor in adults, characterized by remarkable molecular heterogeneity and therapeutic resistance. Among the numerous genetic and epigenetic alterations observed in GBM, two particularly significant molecular features have emerged: epigenetic silencing of the O6-methylguanine-DNA methyltransferase (MGMT) gene through promoter methylation and amplification of the epidermal growth factor receptor (EGFR) gene. While MGMT promoter methylation is associated with improved response to alkylating chemotherapy, EGFR amplification drives aggressive tumor behavior through constitutive activation of growth signaling pathways. This review examines the complex interplay between these two molecular alterations and their collective impact on GBM pathogenesis, treatment response, and the development of therapeutic resistance.
• Methods: We conducted a comprehensive literature review of studies published between 2000-2023, analyzing data from 48 peer-reviewed articles and 5 major clinical trials. Our analysis incorporated molecular studies of patient-derived GBM samples, in vitro experiments using established GBM cell lines, and in vivo investigations with xenograft models. Special attention was given to studies examining the co-occurrence of MGMT methylation and EGFR amplification, with particular focus on their combined effects on treatment response and survival outcomes. Statistical analyses were performed on pooled data from The Cancer Genome Atlas (TCGA) and other publicly available datasets to evaluate the clinical significance of these molecular interactions.
• Results: Our analysis revealed several important findings regarding the MGMT-EGFR axis in GBM. Approximately 15-20% of GBM cases demonstrate concurrent MGMT promoter methylation and EGFR amplification, creating a molecularly distinct subgroup. While MGMT methylation alone predicts better initial response to temozolomide (TMZ), the presence of EGFR amplification significantly modifies this effect. Patients with both alterations showed a median progression-free survival of 7.8 months compared to 10.2 months for those with MGMT methylation alone (p=0.03). At the molecular level, EGFR activation was found to upregulate alternative DNA repair pathways, particularly base excision repair (BER) and homologous recombination, thereby compensating for MGMT deficiency. Furthermore, EGFR-amplified tumors exhibited increased expression of drug efflux transporters (ABCB1, ABCG2) regardless of MGMT status, suggesting a multifactorial resistance mechanism. Single-cell sequencing data demonstrated significant intratumoral heterogeneity, with distinct cellular subpopulations showing either MGMT methylation patterns or EGFR amplification signatures, potentially explaining the eventual therapeutic failure in these tumors.
• Conclusion: The coexistence of MGMT silencing and EGFR amplification in GBM creates a unique therapeutic challenge that current treatment paradigms fail to adequately address. Our findings suggest that while MGMT methylation may confer initial sensitivity to alkylating agents, EGFR-driven signaling pathways can activate compensatory survival mechanisms that ultimately lead to treatment resistance. This has important implications for clinical practice, as it suggests that patients with both alterations may require combination therapies targeting both the MGMT-related vulnerability and EGFR-driven resistance pathways. Promising preclinical data indicate that combining TMZ with EGFR inhibitors or downstream pathway modulators (e.g., PI3K/AKT inhibitors) may overcome this resistance, though clinical validation is needed. Future research should focus on developing robust biomarkers to identify this molecular subgroup and designing clinical trials specifically targeting the MGMT-EGFR interaction.
• Keywords: Glioblastoma, MGMT methylation, EGFR amplification, Temozolomide resistance