Treating glioblastoma with a class of drugs known as EGFR inhibitors increases the cancer’s sensitivity to chemotherapy, a preclinical model study jointly led by researchers at UT Southwestern Medical Center and the University of Alabama at Birmingham suggests. The survey results are scientific translational medicinecould lead to new strategies to combat the most common primary brain tumor in adults.
Glioblastoma is a devastating brain tumor with a poor prognosis and no truly effective treatment. Our research could offer new hope to the approximately 250,000 patients worldwide who are diagnosed with this disease each year. ”
Amin Habib, MD, Professor of Neurology and Neurosurgery, Utah Southwestern University, Staff Physician, Dallas Veterans Affairs Medical Center
Dr. Habib is also a member of the Development and Cancer Research Program at the Harold C. Simmons Comprehensive Cancer Center and an investigator at the Peter O’Donnell Jr. Brain Institute.
Dr. Habib co-led the study with Gao Guo, DDS, MSD, Ph.D., assistant professor of neurosurgery at the University of Alabama at Birmingham and a former postdoctoral fellow in Habib’s lab. The study’s co-lead authors are Arifa Nayab, MPH, a former member of the Habib Institute, and Dr. Nouman Mughal, former assistant professor of surgery at the Aga Khan University in Pakistan.
Despite decades of research, the outcome of glioblastoma remains grim. Most patients survive 12 to 18 months after diagnosis, with a 5-year survival rate of 5 to 7%. Glioblastoma is usually treated with the chemotherapy drug temozolomide (TMZ), along with surgery and radiation therapy. This drug works by damaging the DNA of cancer cells, preventing them from dividing, and ultimately killing them. However, glioblastoma patients who initially respond to TMZ almost inevitably develop incurable, drug-resistant cancers in their brains. There are no effective treatments for recurrent TMZ-resistant glioblastoma.
Researchers have long known that TMZ is most effective against tumors that do not produce a protein called O-6-methylguanine-DNA methyltransferase (MGMT), which repairs DNA damage caused by TMZ. However, TMZ has been shown to increase MGMT over time, so understanding how cells regulate this process could lead to more effective treatments for glioblastoma, Dr. Habib explained.
The Habib Lab has long focused on how epidermal growth factor receptor (EGFR), a protein produced by a gene that is frequently mutated in glioblastomas, causes glioblastomas and several other types of cancer. While studying which molecular pathways are affected by EGFR, Dr. Habib and his colleagues discovered that inhibiting EGFR also significantly reduced the amount of MGMT produced by glioblastoma cells grown in the laboratory. They found similar effects in a mouse model of glioblastoma.
Additional experiments showed that an EGFR inhibitor called afatinib made glioblastoma cells and tumors growing in mice more sensitive to TMZ, even if they had developed TMZ resistance. However, this strategy only worked if the researchers pretreated with afatinib the day before administering TMZ. Dr. Habib said that administering both drugs at the same time had no effect because MGMT production must be stopped by EGFR inhibition before TMZ can do its job.
This finding may explain why clinical trials testing the simultaneous administration of TMZ inhibitors and EGFR inhibitors were unsuccessful, Dr. Habib added. When researchers tested glioblastoma samples taken from patients participating in such trials, they found that the tumor cells contained high levels of MGMT, which blocks the action of TMZ. Glioblastoma samples from another clinical trial testing only novel EGFR inhibitors showed significant reductions in MGMT levels, suggesting that TMZ may be effective after administration of EGFR-targeted drugs.
If future clinical trials confirm that treatment with EGFR inhibitors increases glioblastoma patients’ sensitivity to TMZ, this strategy could eventually become the gold standard for treating this cancer, Dr. Habib said.
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UT Southwestern Medical Center
Reference magazines:
Nayab, A. others. (2026). EGFR inhibition downregulates MGMT and increases responsiveness to temozolomide in glioblastoma. Science translational medicine. DOI: 10.1126/scitranslmed.adx8398. https://www.science.org/doi/10.1126/scitranslmed.adx8398
