Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients
Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients
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DOI：
10.1158/1078-0432.ccr-16-2203
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发表时间：
2017-06-15
影响因子：
11.5
通讯作者：
Grandis, Jennifer R.
中科院分区：
文献类型：
--
作者：
Brand, Toni M.;Hartmann, Stefan;Grandis, Jennifer R.
目的：人乳头状瘤病毒(HPV)16在越来越多的头颈部鳞状细胞癌(HNSCC)中起病因学作用，其中E6和E7癌蛋白的病毒表达是肿瘤生长和维持所必需的。尽管HPV阳性肿瘤患者的预后较好，但目前还没有HPV选择性治疗方法。最近的研究发现在HPV+和HPV-肿瘤中存在不同的受体酪氨酸激酶(RTK)谱。其中一种RTK，HER3，在HPV+肿瘤中过表达，并与磷脂酰肌醇-3-激酶(PI3K)相互作用。因此，我们研究了HPV癌蛋白在调节HER3介导的信号转导中的作用，并确定了HER3是否可以作为HPV+HNSCC的分子靶点。实验设计：使用已建立的细胞系、患者来源的异种移植物(PDX)和人类肿瘤标本来研究HER3作为HPV+HNSCC的分子靶点。通过增加HNSCC细胞株中E6和E7的表达水平，研究了HPV和HER3之间的机制联系。用抗HER3 siRNAs和临床分期抗HER3单抗KTN3379评价HPV+和HPV-HNSCC模型对HER3的依赖性。结果：HER3在HPV+HNSCC中高表达，与咽癌患者的总体生存时间相关。进一步的研究表明，E6和E7调控HER3蛋白的表达和PI3K信号通路的下游。靶向HER3的siRNAs或KTN3379显著抑制HPV+细胞株和PDX的生长。结论：本研究揭示了HPV感染与HER3在HNSCC中的直接关系，为HER3靶向治疗HPV+患者的临床评价提供了理论依据。(C)2016年AACR。
Purpose: Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of head and neck squamous cell carcinomas (HNSCC), where viral expression of the E6 and E7 oncoproteins is necessary for tumor growth and maintenance. Although patients with HPV+ tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV+ versus HPV- tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide-3-kinase (PI3K) in HPV+ tumors. Therefore, we investigated the role of HPV oncoproteins in regulating HER3-mediated signaling and determined whether HER3 could be a molecular target in HPV+ HNSCC.Experimental Design: HER3 was investigated as a molecular target in HPV+ HNSCC using established cell lines, patient-derived xenografts (PDX), and human tumor specimens. A mechanistic link between HPV and HER3 was examined by augmenting E6 and E7 expression levels in HNSCC cell lines. The dependency of HPV+ and HPV- HNSCC models on HER3 was evaluated with anti-HER3 siRNAs and the clinical stage anti-HER3 monoclonal antibody KTN3379.Results: HER3 was overexpressed in HPV+ HNSCC, where it was associated with worse overall survival in patients with pharyngeal cancer. Further investigation indicated that E6 and E7 regulated HER3 protein expression and downstream PI3K pathway signaling. Targeting HER3 with siRNAs or KTN3379 significantly inhibited the growth of HPV+ cell lines and PDXs.Conclusions: This study uncovers a direct relationship between HPV infection and HER3 in HNSCC and provides a rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV+ patients. (C) 2016 AACR.