Researchers at UHN’s Princess Margaret Cancer Centre (PM) showed that mutations in a key pathway (the KEAP1/NRF2 pathway) can drive radiotherapy resistance in head and neck squamous cell carcinomas (HNSCC)—a group of cancers that develop from the cells that line the moist surfaces of the head and neck.
For many solid tumours, including HNSCCs, a type of radiation therapy given from outside the body (external beam radiation) is usually the standard treatment, often combined with chemotherapy. Radiotherapy uses high-energy radiation to kill cancer cells. Understanding why some tumours resist radiation treatment is crucial for improving patient outcomes and reducing disease-related complications.
Approximately 20% of HNSCCs involve mutations in a specific set of genes that form the KEAP1/NRF2 pathway. This pathway typically helps protect cells from damage caused by reactive oxygen species—unstable oxygen molecules that can damage DNA and other cell parts. A key way that radiation therapy works is by generating these reactive oxygen species to kill cancer cells. Mutations in this pathway have previously been linked to a poor response to standard cancer therapies, including radiation therapy.
To investigate this further, the research team, co-led by PM’s Dr. David Kirsch, created specialized experimental models and cell lines that mimic the genetic changes seen in human cancers. They also exposed models to cancer-causing chemicals found in tobacco to mimic real-world environmental risk factors. Tumours were then examined using a variety of lab techniques, and radiation therapy was administered to see how changes in the KEAP1/NRF2 pathway affect both treatment resistance and the immune system’s response.
The team found that tobacco chemicals accelerate the initiation and growth of head and neck tumours. In addition, they found that reduced KEAP1 activity resulted in tumours with stronger NRF2 activation, increased resistance to radiation treatment, more blood vessels feeding the cancer, suppressed immune system function, and reduced survival.
The findings highlight a critical link between genetic changes to the KEAP1/NRF2 pathway and treatment resistance in head and neck cancer. Ongoing studies aim to understand this pathway better and to develop new ways to make radiation treatment work more effectively in people whose cancers carry these genetic changes.
Dr. Rutulkumar Patel, Assistant Professor at Baylor College of Medicine, is the first author of the study.
Dr. Yvonne M. Mowery, Associate Professor of Radiation Oncology at UPMC Hillman Cancer Center, is a co-senior author of the study.
Dr. David Kirsch, Senior Scientist at Princess Margaret Cancer Centre (PM), Allan Slaight Scientist at PM, Peter and Shelagh Godsoe Chair in Radiation Medicine, and Professor in the Departments of Medical Biophysics and Radiation Oncology at the University of Toronto, is a co-senior author of the study.
This work was supported by the National Institutes of Health, the American Cancer Society, the National Cancer Institute, Veterans Affairs (USA), the National Institute of Allergy and Infectious Diseases, the Cancer Prevention and Research Institute of Texas (CPRIT), and The Princess Margaret Cancer Foundation.
Dr. Yvonne Mowery has leadership roles in ASTRO and NRG Oncology, receives grant funding from the National Institutes of Health, the Damon Runyon Cancer Research Foundation, and Stand Up to Cancer (SU2C), and receives an honorarium from the University of Wisconsin-Madison.
Dr. David Kirsch reports grant funding from the National Cancer Institute (NCI), in support of the research described in this manuscript. In the past, he has received support from the Merck Investigator Studies Program, SU2C, Bristol Myers Squibb, Varian Medical Systems, and the Department of Defense. He also receives other National Institutes of Health (NIH) funding not related to this work. Dr. Kirsch holds a license for an imaging device through Lumicell Inc., and patents through Lumicell Inc. and XRad Therapeutics. He served on the Scientific Advisory Board of Lumicell Inc., and holds stock in XRad Therapeutics and Lumicell Inc.
See the manuscript for the complete list of competing interests.
Patel R, Saab K, Luo L, Ma Y, Osman RA, Williams NT, Everitt J, Zelazowski MJ, Castro P, Decker WK, Hudson WH, Myers JN, Sandulache VC, Frederick MJ, Mowery YM, Kirsch DG. Nrf2 hyperactivation as a driver of radiotherapy resistance and suppressed anti-tumor immunity in head and neck squamous cell carcinoma. Clin Cancer Res. 2025 Jul 31. doi: 10.1158/1078-0432.CCR-25-0112. Epub ahead of print.