EGFR inhibition down-regulates MGMT and enhances responsiveness to temozolomide in glioblastoma

Authors

• Arifa Nayab, University of Texas Southwestern Medical Center, Dallas
• Nouman Mughal, Aga Khan University
• Meher Angez, Aga Khan UniversityFollow
• Fazal M. Arain, Aga Khan UniversityFollow
• Azhar Hussain, Aga Khan UniversityFollow
• Ather Enam, Aga Khan UniversityFollow
• Mansoor Saleh, Aga Khan UniversityFollow

Document Type

Article

Department

Surgery; Biological and Biomedical Sciences

Abstract

Glioblastoma (GBM) is a devastating cancer with a dismal prognosis. Current treatment includes temozolomide (TMZ), which is more effective in about 50% of GBMs that have O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. MGMT is a DNA repair protein that reverses TMZ-induced DNA damage. EGFR is a prime oncogene in GBM. Here, we report that EGFR inhibition induced the down-regulation of MGMT in GBM cells, revealing a previously unidentified link between EGFR signaling and response to TMZ. EGFR inhibition led to activation of two transcription factors, activator protein-1 (AP-1), which repressed MGMT transcription, and nuclear factor κB (NF-κB), which up-regulated MGMT transcription. EGFR inhibition also induced AP-1-mediated transcription of miR-616. miR-616 inhibited both MGMT translation and NF-κB activation. Thus, the overall effect of EGFR inhibition was down-regulation of MGMT expression. In addition, we provided an explanation for the prior failure of clinical trials that used concomitant EGFR tyrosine kinase inhibitors (TKIs) and TMZ. TMZ up-regulated MGMT, and concomitant treatment with EGFR TKIs and TMZ failed to down-regulate MGMT. However, pretreatment with EGFR TKIs followed by TMZ efficiently down-regulated MGMT and enhanced TMZ sensitivity in experimental models. Posttreatment tumor tissues from two clinical trials were used to validate these findings. We demonstrated that EGFR inhibitors induced down-regulation of MGMT in posttreatment resected tumor tissues from patients with GBM and the failure of EGFR inhibition to down-regulate MGMT if TMZ was used concomitantly. These data support using EGFR TKIs before TMZ treatment as a therapeutic approach in MGMT unmethylated GBM.

Comments

Pagination is not provided by the author/publisher.

Publication (Name of Journal)

Sci Transl Med

DOI

10.1126/scitranslmed.adx8398

Recommended Citation

Nayab, A., Mughal, N., Angez, M., Arain, F. M., Hussain, A., Enam, A., Saleh, M. (2026). EGFR inhibition down-regulates MGMT and enhances responsiveness to temozolomide in glioblastoma. Sci Transl Med, 18(857).
Available at: https://ecommons.aku.edu/pakistan_fhs_mc_surg_surg/982