Department of Molecular Oncology, Centre for Host Microbiome Interaction, King's College London, Guy's Hospital Campus, London, SE1 1UL, UK; Department of Basic and Clinical Sciences, Umm Al-Qura University, Faculty of Dentistry, Makkah, 2373, Saudi Arabia.
Department of Head and Neck Pathology, Centre for Clinical, Oral and Translational Science, Guy's Hospital Campus, King's College, London, SE1 9RT, UK.
Cancer Lett. 2021 Feb 1;498:80-97. doi: 10.1016/j.canlet.2020.10.035. Epub 2020 Oct 31.
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.
高危型人乳头瘤病毒（HPV）感染已成为头颈部鳞状细胞癌（HNSCC）的一个独立危险因素。HPV 诱导的 HNSCC 亚型的发病率显著增加，其具有不同的遗传学特征，治疗效果更好。尽管 HPV-HNSCC 的预后良好，但包括高剂量放疗（RT）联合化疗（CT）在内的治疗方式与 HPV 阴性肿瘤相似，伴随毒性副作用。表皮生长因子受体（EGFR）在超过 80%的 HNSCC 中过表达，并与 RT 抵抗相关。EGFR 抑制剂西妥昔单抗是唯一 FDA 批准用于两种 HNSCC 亚型的靶向治疗药物，但对 HNSCC 亚型的反应不同。在 HPV 阴性 HNSCC 中，西妥昔单抗使 HNSCC 对 RT 敏感，提高了生存率。为了减少 CT 的不良反应毒性，西妥昔单抗已被批准用于治疗 HPV 阳性 HNSCC 的降阶治疗。几项最近的临床试验的结果得出了与 HPV 阴性 HNSCC 不同的结论。在这里，我们研究了 EGFR 在 HPV 阳性 HNSCC 对 RT 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 激活强烈表明 RT 反应增加。对 RT 的反应中，EGFR 激活诱导 DNA 损伤修复受损，并增加 RT 反应。此外，发现 EGFR 下调 HPV 癌蛋白 E6 的表达，并在 RT 反应中诱导 p53 活性。总的来说，我们的数据揭示了 EGFR 在病毒诱导的 HNSCC 中的新作用，并强调了在癌症的遗传构成背景下使用 EGFR 靶向治疗的重要性。
