Dr Yi Ye and Dr Vanessa Uzonwan examine research that suggests how cancer drugs may be repurposed to manage oral cancer pain. 

Cancer-associated pain remains a major clinical challenge, particularly in oral squamous cell carcinoma (OSCC), where patients experience severe pain during eating and speaking alongside substantial declines in quality of life. Despite advances in pain research, management still relies largely on opioids. Although opioids can provide initial relief, escalating doses are often required as tolerance develops, leading to reduced efficacy and increased risks of dependence and systemic toxicity. Patients with OSCC are particularly vulnerable to opioid tolerance and opioid-induced toxicities due to high baseline pain levels and advanced age. These limitations underscore a persistent unmet need in cancer pain therapeutics. 

Emerging evidence indicates that tumour biology and the nervous system are tightly interconnected, and that oral cancer pain mechanisms extend beyond tissue injury and inflammation. The epidermal growth factor receptor (EGFR), classically associated with tumour proliferation, is increasingly recognised as a contributor to neuronal excitability in sensory neurons under painful conditions. Our recent work demonstrates a functional interaction between EGFR and N-methyl-D-aspartate receptors (NMDARs) in trigeminal ganglion (TG) neurons, promoting oral cancer pain amplification and priming the system for reduced opioid responsiveness — potentially explaining the rapid development of tolerance. These findings open up new translational opportunities.

EGFR–NMDAR pathway: linking tumour biology and neuronal sensitisation

The oral tumour microenvironment contains multiple EGFR ligands, including HB-EGF and TGF-α, that activate EGFR signalling in cancer cells, where the receptor is frequently overexpressed or mutated and drives tumour growth, invasion, and metastasis. Importantly, sensory neurons innervating oral tumours also exhibit elevated EGFR expression. EGFR activation enhances neuronal excitability through direct modulation of NMDAR function, a receptor critical for excitatory synaptic transmission and implicated in pain facilitation, opioid tolerance, and neurotoxicity. Mechanistically, EGFR signalling promotes NMDAR phosphorylation and augments both pre- and postsynaptic activity within trigeminal circuits. 

Clinically, NMDAR antagonists such as memantine and ketamine can reduce neuropathic pain and mitigate opioid tolerance, supporting the importance of this pathway, although their use is constrained by adverse effects. Interestingly, in pancreatic ductal adenocarcinoma, EGFR-expressing sensory neurons innervating tumours form synapses-like connections with cancer cells, promoting tumour growth and dissemination through glutamate-NMDAR signalling. These findings, together with ours, suggest that as tumours progress and ligand availability increases, neuronal EGFR signalling may become further amplified, which could drive a feedforward loop to amplify glutamate signalling in cancer cells, offering a mechanistic explanation for the correlation between tumour burden and pain severity. These suggest that cancer pain reflects shared signalling drivers operating across both tumour and neuronal compartments.

Translational implications

A notable strength of this mechanism is its linkage to an established clinical target. EGFR inhibitors—including small-molecule tyrosine kinase inhibitors and monoclonal antibodies—are already widely used in oncology, with well-defined pharmacokinetics, dosing strategies, and safety profiles. Rather than initiating de novo analgesic development, repurposing these agents for cancer pain could accelerate translation by leveraging existing regulatory approvals and manufacturing infrastructure. 

This approach may offer a potential triple benefit: suppression of tumour-driven growth signalling, attenuation of pain, and reduction in opioid requirements. In OSCC, where EGFR overexpression is common, such multipurpose application may be particularly advantageous. Nonetheless, careful consideration of dose, treatment duration, and patient selection is necessary given EGFR’s roles in physiological processes beyond tumour growth and pain modulation. 


Precision considerations: ligand context and pathway complexity 


EGFR signalling is inherently ligand- and context-dependent. Although existing studies have focused on individual ligands, the tumour microenvironment contains a dynamic mixture capable of synergistic, additive, or competitive modulation of neuronal EGFR activity. This complexity creates opportunities for precision medicine. EGFR ligand expression can vary substantially across patients, underscoring the importance of individualised dosing strategies to optimise therapeutic efficacy while minimising toxicities associated with EGFR inhibitors. Moreover, ligand composition may differ across tumour types and disease stages, potentially shaping NMDAR sensitisation and pain phenotypes. Accordingly, biomarker-driven approaches based on EGFR expression or ligand abundance could help identify patients most likely to benefit from EGFR-targeted analgesic interventions. 

Moreover, EGFR engages diverse downstream signaling pathways beyond those presently defined. Systematic mapping of these networks may enable selective suppression of pathological neuronal hyperexcitability while preserving essential physiological signalling, providing a conceptual framework for therapeutic stratification.

Looking ahead

Linking a well-established oncogenic pathway to a persistent clinical problem in pain management highlights a promising direction for drug discovery. Continued exploration of tumour – neuron signalling interfaces may uncover additional opportunities to repurpose oncology targets for cancer pain treatment. Integrating mechanistic insight with translational strategies has the potential to limit opioid escalation and ultimately improve quality of life for patients with oral cancer and other malignancies.

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About the authors:

Dr Yi Ye serves as an Associate Professor and Associate Director at the Translational Research Center within the NYU College of Dentistry. Holding additional appointments in the Pain Research Center, NYU College of Dentistry and the Department of Biomedical Engineering at the NYU Tandon School of Engineering, Dr Ye leads a multidisciplinary team focused on the cellular, molecular, and biophysical mechanisms of pain associated with cancer and its treatments.  

Dr Vanessa Uzonwanne is a postdoctoral associate whose current research focuses on the complexities of chemotherapy-induced peripheral neuropathy. Together, the Ye Lab is dedicated to translating mechanistic insights into clinically actionable strategies that improve pain management and reduce treatment-related neuropathy for cancer patients.