New research published in Science Signaling reveals that epidermal growth factor receptor (EGFR) signaling in tissues surrounding oral tumors plays a dual role: intensifying pain sensitivity and reducing the effectiveness of opioid analgesics. These findings identify a shared biological mechanism behind oral cancer pain and opioid tolerance, offering a potential new therapeutic approach.
Led by Yi Ye, PhD, associate professor at NYU College of Dentistry, the study highlights the urgent need for improved pain management strategies. Oral cancer causes severe pain that interferes with basic functions such as eating and speaking. Although opioids remain the standard treatment, patients often require escalating doses and develop tolerance rapidly, increasing the risk of adverse effects.
The researchers found that EGFR is highly overexpressed in oral cancer–associated nerves, including the trigeminal ganglia. Cancer cells and nearby glial cells release EGFR-activating ligands, triggering downstream signaling that increases nerve excitability. This process also enhances activity of NMDA receptors (NMDARs), which are known contributors to both pain amplification and opioid tolerance.
In mouse models, EGFR activation heightened pain and diminished morphine’s analgesic effects. Conversely, treatment with EGFR inhibitors reduced pain and restored opioid responsiveness. Because EGFR inhibitors are already FDA-approved for various cancers, the findings support their potential repurposing as a non-opioid, mechanism-based therapy for oral cancer pain.
