New research published in Science Signaling identifies epidermal growth factor receptor (EGFR) signaling as a shared biological mechanism driving both oral cancer pain and reduced responsiveness to opioid analgesics. The findings suggest that blocking EGFR signaling—using drugs already approved for cancer treatment—could help address two persistent clinical challenges: managing severe oral cancer pain and limiting opioid tolerance.
According to the study, EGFR signaling in tissues surrounding oral tumors increases nerve sensitivity while also diminishing the effectiveness of opioids. The results indicate that a single pathway may underlie both pain amplification and opioid tolerance, opening the door to a unified treatment approach.
“Repurposing existing cancer drugs that block EGFR may be a promising way to manage oral cancer pain and prevent or reverse opioid tolerance,” said Yi Ye, PhD, associate professor at NYU College of Dentistry and associate director of clinical research operations at NYU Dentistry’s Translational Research Center.
Rethinking the standard approach to cancer pain
Oral cancer pain can be severe, interfering with basic functions such as eating, drinking, and speaking. Although opioids remain widely regarded as the standard treatment, patients with oral cancer often require high doses and tend to develop tolerance more rapidly than patients with other chronic pain conditions.
“In the field of pain research, we struggle with the fact that—even after all these decades of research—the best drug on the market is often still opiates, which come with many risks,” said Ye, the study’s senior author and a faculty member at the NYU Pain Research Center.
As tumors grow, pain severity often increases, suggesting overlapping molecular drivers of both cancer progression and pain. This connection has prompted researchers to explore shared mechanisms that could be targeted therapeutically.
“We are increasingly finding that cancer and the nervous system are interconnected. In my lab, we're trying to address whether there's a common, overlapping mechanism between cancer and pain,” added Ye.
EGFR as a driver of pain and reduced opioid response
EGFR is a cell-surface protein involved in cell growth and division and is overexpressed in most oral cancers. Several FDA-approved EGFR inhibitors are already used to treat multiple cancer types, including oral cancer. Prior research has shown that some patients receiving EGFR inhibitors experience rapid pain relief, and other studies have implicated EGFR signaling in pain conditions and opioid tolerance.
In the Science Signaling study (https://www.science.org/doi/10.1126/scisignal.adt3026), researchers from NYU Dentistry, The University of Texas MD Anderson Cancer Center, and Loma Linda University School of Dentistry examined human oral cancer tissue samples and mouse models. They found that cancer cells and nearby glial cells secreted EGFR ligands, which activated EGFR in surrounding nerves.
EGFR was overexpressed in nerves associated with oral tumors, including trigeminal ganglia. Activation of EGFR also drove hyperactivity of the glutamate N-methyl-d-aspartate receptor (NMDAR), a receptor known to play a critical role in pain signaling and the development of opioid tolerance, in both trigeminal ganglia and the brainstem.
In mouse studies, EGFR activation increased pain and reduced the analgesic effect of morphine. Administration of an EGFR inhibitor, however, reduced pain and restored morphine’s effectiveness.
“These results are clinically significant and reveal a link between EGFR signaling and NMDAR hyperactivity, a mechanism that heightens pain signaling and reduces the effectiveness of opioid analgesics,” said Hui-Lin Pan, MD, PhD, professor of anesthesiology and perioperative medicine at MD Anderson.
Implications for drug repurposing
Because EGFR inhibitors are already widely studied and used in oncology, researchers note that their safety profiles are well understood. The study suggests these agents could reduce pain and opioid requirements while also targeting tumor growth.
"This study provides a rationale for repurposing FDA-approved EGFR inhibitors already used to treat oral cancers, shifting from symptomatic suppression to mechanistic intervention. This approach may offer dual benefits, controlling cancer while addressing pain through a non-opioid, biologically rational approach that could dramatically improve quality of life," said Moran Amit, MD, PhD, assistant professor of head and neck surgery at MD Anderson.
The research team is continuing to investigate EGFR signaling by analyzing patient tumor and blood samples alongside self-reported pain scores and opioid use. Researchers also plan to retrospectively assess pain outcomes in an existing clinical trial of EGFR inhibitors for oral cancer.
“In drug development, it can take decades for a new compound to actually reach the market. If our mechanism holds true in future studies, repurposing EGFR inhibitors is appealing because it could lead to rapid translation and quickly help patients,” said Ye.
"These findings could significantly impact the way we treat cancer pain, providing a targeted approach that mitigates the detrimental side effects seen with opioids. This new treatment approach provides hope to both patients and clinicians treating oral cancer alike," said Chi Viet, DDS, MD, PhD, associate professor of oral and maxillofacial surgery at Loma Linda University School of Dentistry.
The study was supported by the National Institute of Dental and Craniofacial Research and included collaborators from NYU Dentistry, MD Anderson, and Loma Linda University School of Dentistry.
Figures and Images
