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Data from: EGFR inhibition downregulates MGMT through regulation of miRNA 616 and activation of AP-1 and enhances responsiveness to temozolomide in glioblastoma

Nayab, Arifa1; Nouman, Muhammad2; Majd, Nazanin3; Kizilbash, Sani4; Arain, Fazal2; Hussain, Azhar2; Xing, Sansi1; Zhao, Dawen5; Somani, Saif2; Burma, Sandeep6; Youssef, Michael1; Nabors, Louis7; Shaikh, Nawal2; Saleh, Mansoor8; Patel, Toral1; Yang, Xiaoyao1; Hatanpaa, Kimmo1; Singh, Deepti1; Jimenez, Fatima7; Burma, Aarohan1; Balla, Harshitha1; Sarkaria, Jann4; Miller, C.7; Karmali, Alyiah2; Angez, Meher2; Maqbool, Muhammad Asad2; Amir, Sahara2; Patel, Ankur1; Kataru, Mary7; Enam, Syed Ather2; Charest, Alain9; Ye, Carissa1; Tolbert, Chandler7; Habib, Amyn1; Guo, Gao7

Published Jul 08, 2026 on Dryad. https://doi.org/10.5061/dryad.905qfttx0

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Abstract

Glioblastoma (GBM) is a devastating cancer with a dismal prognosis. The standard of care includes treatment with temozolomide (TMZ), a drug that is more effective in approximately 50% of GBMs that have MGMT promoter methylation. MGMT is a DNA repair protein that reverses TMZ-induced DNA damage, and increased MGMT expression in tumor cells is a key determinant of treatment failure. EGFR is a prime oncogene in GBM. Here, we report that EGFR inhibition induces a downregulation of MGMT in GBM cells, revealing a new link between EGFR signaling and the chemotherapeutic response to TMZ. The EGFR TKI-induced downregulation of MGMT results from a complex interplay in which EGFR inhibition leads to activation of two transcription factors, AP-1, which represses MGMT transcription, and NF-kappaB, which upregulates MGMT transcription. EGFR inhibition also induces an AP-1-mediated transcription of miR-616. miR-616 inhibits both MGMT translation and NF-kappaB activation. Thus, the overall effect of EGFR inhibition is downregulation of MGMT expression. If the MGMT inhibitory module comprising AP-1 and miR-616 is blocked, EGFR TKIs now upregulate MGMT via an unopposed activation of NF-kappaB. Additionally, we provide an explanation for the prior failure of clinical trials that have used concomitant EGFR TKIs plus TMZ. TMZ upregulates MGMT, and concomitant treatment with EGFR TKIs plus TMZ fails to downregulate MGMT. However, pretreatment with EGFR TKIs followed by TMZ efficiently downregulates MGMT and enhances their sensitivity to TMZ in experimental models. Importantly, we used post-treatment tumor tissue from two clinical trials to validate these findings. We demonstrate an EGFR inhibitor-induced downregulation of MGMT in post-treatment resected tumor tissue from GBM patients, and also demonstrate a failure of EGFR inhibition to downregulate MGMT if TMZ was used concomitantly. We propose using EGFR TKIs prior to administration of TMZ as a therapeutic approach in MGMT unmethylated GBMs, both in a neo-adjuvant and/or a recurrent setting.