Epidermal growth factor receptor (EGFR) signaling in tissue around oral cancers increases nerve sensitivity and makes opioids less effective, according to new research published in Scientific Signaling.
The findings point to a common mechanism underlying both oral cancer pain and opioid tolerance—and a potential new therapeutic strategy for both.
Repurposing existing anticancer drugs that block EGFR may be a promising way to manage oral cancer pain and prevent or reverse opioid tolerance.”
Yi Ye, PhD, Associate Professor at NYU College of Dentistry and Associate Director of Clinical Research Operations at NYU Dentistry’s Translational Research Center
The need for a new “gold standard”
Oral cancer can be extremely painful, making it difficult for patients to eat, drink and speak. Despite the known side effects and risk of addiction, opioids are still considered by experts to be the gold standard for treating oral cancer pain. In order to effectively manage this pain, patients often require high doses of opioids and develop tolerance more quickly than those with other forms of chronic pain, requiring increasingly large doses to manage it.
“In pain research, we struggle with the fact that—even after all these decades of research—the best medicine on the market is often opiates, which carry many risks,” said Ye, senior author of the study and a faculty member at the NYU Pain Research Center.
When people with cancer experience pain, the severity of the pain tends to increase as the tumor grows, suggesting that there may be common molecular drivers behind the two processes—ones that could be targeted to manage both cancer and pain.
“We are increasingly finding that cancer and the nervous system are interconnected. In my lab, we are trying to examine whether there is a common, overlapping mechanism between cancer and pain,” Ye added.
A mechanism that leads to both pain and tolerance
EGFR, a protein found on the surface of certain cells involved in promoting cell growth and division, has emerged as an important target in cancer therapy. The receptor is overexpressed in most oral cancers, and several FDA-approved drugs that block or inhibit EGFR are used to treat lung, breast, colon, pancreatic, and oral cancers.
Specifically, some research shows that when patients take EGFR inhibitors to treat their cancer, they also experience rapid pain relief. Additional studies point to a role for EGFR in other pain conditions and in opioid tolerance.
At Scientific Signaling study, the research team from NYU Dentistry, the University of Texas MD Anderson Cancer Center and Loma Linda University School of Dentistry studied human tissue samples from oral cancer patients as well as mice with oral cancer to better understand the role of EGFR signaling. In both human and mouse cells, they found that cancer cells and nearby glial cells secreted EGFR ligands, the molecules that activate the receptors.
EGFR was overexpressed in human and mouse nerves associated with oral cancer tumors, including the trigeminal ganglia, the main sensory nerve cells in the face and mouth. This EGFR activation also led to N-methyl-d-aspartate glutamate receptor (NMDAR) signaling and hyperactivity—a well-studied pain signaling receptor thought to play a critical role in the development of opioid tolerance—in the trigeminal ganglia and brainstem.
In additional studies in mice, researchers found that EGFR ligands that activate the receptor in the trigeminal system increased pain and made morphine less effective. In contrast, giving the mice an EGFR inhibitor drug reduced pain and restored the analgesic effects of morphine.
“These results are clinically relevant and reveal a link between EGFR signaling and NMDAR hyperactivity, a mechanism that enhances pain signaling and reduces the efficacy of opioid analgesics,” said study author Hui-Lin Pan, MD, PhD, professor of anesthesiology and perioperative medicine at MD Anderson.
Repurposing drugs to fight cancer
This new mechanistic understanding of oral cancer pain and opioid tolerance suggests a new and not-so-new approach to better manage oral cancer pain: EGFR inhibitors. Because these drugs have been widely studied as cancer treatments, researchers already know about their safety and side effects. In addition, EGFR inhibitors may reduce pain and the need for more opioids while controlling the cancer.
“This study provides a rationale for repurposing the FDA-approved EGFR inhibitors already used to treat oral cancer, moving from symptomatic suppression to mechanistic intervention. This approach may offer dual benefits, controlling cancer while treating pain through a non-opioid, biologically rational approach that could dramatically improve the head’s quality of life,” said the professor. at MD Anderson.
Researchers are continuing to examine the role of EGFR and its ligands in oral cancer pain and opioid tolerance by analyzing patient tumor and blood samples, along with self-reported pain scores and opioid use. In addition, leveraging an existing clinical trial for EGFR inhibitors in the remission of oral cancer, the team plans to retrospectively evaluate the effect of EGFR inhibitors on pain relief using clinical records.
“In drug development, it can take decades for a new compound to reach the market. If our mechanism holds true in future studies, repurposing EGFR inhibitors is attractive because it could lead to rapid translation and help patients quickly,” said Ye.
“These findings could significantly impact the way we treat cancer pain by providing a targeted approach that mitigates the harmful side effects seen with opioids. This new therapeutic approach provides hope for both patients and clinicians dealing with oral cancer alike,” said study author Chi Viet, DDS, MD, PhD, associate professor of oral and maxillofacial surgery at Loma Lindrya University.
Additional study authors include Naijiang Liu, Xiaojie Shi, Maria Daniela Santi, Maria Fernanda Pessano Fialho, Rocco Latorre and Nigel Bunnett of NYU Dentistry. Shao-Rui Chen, Hong Chen, Tongxin Xie, and Frederico Gleber-Netto of MD Anderson. and Dong Minh Phuong of Loma Linda University School of Dentistry. The research was supported by the National Institute of Dental and Craniofacial Research (R01DE032501, RM1DE033491).
