EGFR overexpression increases radiotherapy response in HPV-positive head and neck cancer through inhibition of DNA damage repair and HPV E6 downregulation
EGFR overexpression increases radiotherapy response in HPV-positive head and neck cancer through inhibition of DNA damage repair and HPV E6 downregulation
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DOI：
10.1016/j.canlet.2020.10.035
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发表时间：
2021-02-01
期刊：
影响因子：
9.7
通讯作者：
Tavassoli, Mahvash
中科院分区：
文献类型：
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作者：
Alsahafi, Elham Nafea;Thavaraj, Selvam;Tavassoli, Mahvash
高危人乳头瘤病毒（HPV）感染最近成为头颈部鳞状细胞癌（HNSCC）的独立危险因素。hpv诱导的HNSCC亚型的发病率显著增加，这表明不同的遗传学有更好的治疗效果。尽管HPV-HNSCC预后良好，但其治疗方式，即高剂量放疗（RT）联合化疗（CT），仍然与hpv阴性肿瘤相似，并伴有毒副作用。表皮生长因子受体（EGFR）在80%以上的HNSCC中过表达，并与RT耐药性相关。EGFR抑制剂西妥昔单抗是FDA批准的唯一针对两种HNSCC亚型的靶向治疗药物，然而不同HNSCC亚型的疗效不同。在hpv阴性的HNSCC中，西妥昔单抗使HNSCC对RT敏感，提高了生存率。为了降低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了hpv阴性HNSCC的不同结果。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。在RT反应中，EGFR激活诱导DNA损伤修复损伤和RT反应增加。此外，EGFR被发现下调HPV癌蛋白6的表达并诱导p53活性，以响应rt。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，并强调了在癌症基因构成背景下使用EGFR靶向治疗的重要性。
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.