Shared process underlies oral cancer pain and opioid tolerance

Epidermal growth factor receptor (EGFR) signaling in the tissue around oral cancers both increases nerve sensitivity and makes opioids less effective, according to new research published in Science Signaling.

The findings point to a shared mechanism underlying both oral cancer pain and opioid tolerance—and a possible new treatment strategy for both. 

“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.

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 well-known side effects and risk for addiction, opioids are still seen by experts as the gold standard for treating oral cancer pain. In order to effectively manage this pain, patients often need high doses of opioids and develop tolerance more quickly than those with other forms of chronic pain, requiring larger and larger doses to treat it.

“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. 

When people with cancer experience pain, the severity of the pain tends to increase as a tumor grows, suggesting that there may be shared molecular drivers behind both 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're trying to address whether there's a common, overlapping mechanism between cancer and pain,” added Ye.

A mechanism driving 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 treatment. 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. 

Notably, some research shows that when patients receive EGFR inhibitors to treat their cancers, they also experience rapid pain relief. Additional studies point to EGFR’s role in other pain conditions and in opioid tolerance.

In the Science 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 patients with oral cancer 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 in trigeminal ganglia, the main sensory nerve cells in the face and mouth. This EGFR activation also drove signaling and hyperactivity of the glutamate N-methyl-d-aspartate receptor (NMDAR)—a well-studied pain signaling receptor that is thought to play a critical role in the development of opioid tolerance—in trigeminal ganglia and the brainstem.

In additional studies in mice, the 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 both reduced pain and restored the analgesic effects of morphine.

“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 study author Hui-Lin Pan, MD, PhD, professor of anesthesiology and perioperative medicine at MD Anderson.

Repurposing cancer-fighting drugs

This new mechanistic understanding of oral cancer pain and opioid tolerance suggests a new—and not-so-new—approach to better treating oral cancer pain: EGFR inhibitors. Because these drugs have been widely studied as cancer treatments, researchers already know about their safety and side effects. Moreover, EGFR inhibitors might reduce pain and the need for more opioids while also controlling the cancer.

"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 researchers are continuing to look at the role of EGFR and its ligands in oral cancer pain and opioid tolerance by analyzing patients’ tumor and blood samples, alongside self-reported pain scores and opioid use. In addition, leveraging an existing clinical trial on EGFR inhibitors in oral cancer regression, the team plans to retrospectively evaluate the impact of EGFR inhibitors on pain relief using clinical records.

“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 study author Chi Viet, DDS, MD, PhD, associate professor of oral and maxillofacial surgery at Loma Linda University School of Dentistry.

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).

 

###

---

---