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

Authors

Arifa Nayab, Nouman Mughal, Meher Angez, Sansi Xing, Aarohan M Burma, Harshitha Balla, Sani H Kizilbash, Xiaoyao Yang, Muhammad Asad Maqbool, Fazal Arain, Azhar Hussain, Sahara Amir, Deepti Singh, Alyiah Karmali, Saif Somani, Toral R Patel, Ankur Patel, Kimmo J Hatanpaa, Michael Youssef, Nawal Shaikh, Carissa Ye, Dawen Zhao, Sandeep Burma, Jann N Sarkaria, Nazanin K Majd, Mansoor Saleh, Alain Charest, C Ryan Miller, Louis B Nabors, Mary Susmitha Kataru, Chandler E Tolbert, Fatima Jimenez, Syed Ather Enam, Amyn A Habib, Gao Guo

Published in

Science translational medicine. Volume 18. Issue 857. Pages eadx8398. Jul 08, 2026. Epub Jul 08, 2026.

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.

PMID:
42418561
Bibliographic data and abstract were imported from PubMed on 09 Jul 2026.

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