The Role of EGF Receptor Signalling in HPV-derived HNSCC Response to Radiotherapy

Abstract

Head and neck squamous cell carcinoma (HNSCC), a group of heterogeneous cancers, represent an aggressive molecular biology and treatment challenge. These cancers develop near critical anatomical structures in the head and neck, which are sensitive to treatment, resulting in severe toxicities and reduced quality of life. High-risk Human Papilloma Virus (HPV) infections have recently emerged as an independent risk factor in HNSCC. There has been a marked increase in the incidence of HPV-positive HNSCC subtype. The HPV-induced tumours demonstrate different genetics and have favourable prognosis, however the treatment modality, which is mainly, high dose radiotherapy (RT) in combination with chemotherapy, is similar to HPV-negative tumours and is associated with severe adverse side effects. Epidermal growth factor receptor (EGFR) is overexpressed in more than 80% of HNSCC resulting in increased proliferation, survival, angiogenesis and is known to play an important role in HNSCC therapy resistance. EGFR inhibitor Cetuximab is the only FDA-approved targeted therapy for both HNSCC subtypes, though the response seems to be different between the two molecular subtypes. In HPV-negative tumours, EGFR overexpression is correlated with RT resistance and EGFR inhibitor Cetuximab sensitises HNSCC to radiotherapy and improves survival rates. The precise role of EGFR in HPV-positive HNSCC is unclear, nonetheless for the purpose of reducing adverse cytotoxicity of chemotherapy Cetuximab has been used for treatment de-intensification of HPV-positive HNSCC, but the results of several large-scale clinical trials have concluded surprising and differing outcome to HPV- negative cancers. This study investigated the role of EGFR in HPV-positive HNSCC cell lines particularly its role in radiotherapy response. The study results showed that EGFR signalling pathway is differentially regulated in HPV-derived HNSCC. In contrary to HPV-negative cancers, where EGFR activates DNA repair, in HPV-positive HNSCC cell lines EGFR activation strongly inhibited radiation-induced DNA repair resulting in enhanced radiosensitivity. EGFR was also found to significantly reduce HPV16-E6 expression resulting in restoration of p53 activity and induction of cell death. Notably, EGFR showed a differing regulatory role in modulating tumour- derived exosomes in HNSCC subtypes. The data presented in this study demonstrated an alternative role for EGFR in virally derived HNSCC cells and highlighted the importance of considering using EGFR-targeted therapy in the context of the genetic makeup of the tumour.