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

最近，高危型人乳头瘤病毒（HPV）感染已成为头颈部鳞状细胞癌（HNSCC）的独立危险因素。HPV诱导的HNSCC亚型的发生率显着增加，这表明遗传学不同，治疗效果更好。尽管HPV-HNSCC的预后良好，但包括高剂量放疗（RT）结合化学疗法（CT）的治疗方式仍与HPV阴性肿瘤相似，并伴有毒性副作用。表皮生长因子受体（EGFR）在HNSCC的80％以上过表达，并与RT耐药相关。EGFR抑制剂西妥昔单抗是FDA批准的两种HNSCC亚型的唯一靶向治疗药物，但是HNSCC亚型之间的反应有所不同。在HPV阴性HNSCC中，西妥昔单抗可使HNSCC对RT敏感，从而提高生存率。为了减少CT的不良细胞毒性，西妥昔单抗已被批准用于治疗HPV阳性HNSCC的降级。最近几项临床试验的结果得出结论，与HPV阴性HNSCC的结果不同。在这里，我们研究了EGFR在HPV阳性HNSCC对RT的反应中的作用。值得注意的是，在HPV阳性HNSCC细胞系和体内肿瘤模型中，EGFR激活强烈指示RT反应增加。响应RT，EGFR激活引起DNA损伤修复受损，RT反应增加。此外，发现EGFR下调HPV癌蛋白E6表达并诱导对RT的p53活性。总的来说，