EGFR overexpression increases radiotherapy response in HPV-positive head and neck cancer through inhibition of DNA damage repair and HPV E6 downregulation

High-risk Human Papillomavirus (HPV) infections have recently emerged as an independent risk factor in head and neck squamous cell carcinoma (HNSCC). There has been a marked increase the incidence of HPV-induced HNSCC subtype, which demonstrates different genetics with better treatment outcome. Despite favourable prognosis HPV-HNSCC, modality, consisting high dose radiotherapy (RT) combination chemotherapy (CT), remains similar to HPV-negative tumours, associated toxic side effects. Epidermal growth receptor (EGFR) is overexpressed over 80% correlates RT resistance. EGFR inhibitor Cetuximab only FDA approved targeted therapy for both subtypes, however response varies between subtypes. In HNSCC, sensitises improving survival rates. To reduce adverse cytotoxicity CT, de-escalation HPV-positive HNSCC. The results several recent clinical trials concluded differing outcome Here we investigated role RT. Remarkably, lines vivo tumour models, activation was strongly indicative increased response. RT, induced impairment DNA damage repair Furthermore, found downregulate HPV oncoproteinE6 expression p53 activity Collectively, our data uncovers novel virally highlights importance using EGFR-targeted therapies context genetic makeup cancer.