Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV + Patients

Clin Cancer Res. 2017 Jun 15;23(12):3072-3083. doi: 10.1158/1078-0432.CCR-16-2203. Epub 2016 Dec 16.

Abstract

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. Clin Cancer Res; 23(12); 3072-83. ©2016 AACR.

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / virology
  • Cell Line, Tumor
  • Elafin / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Viral / genetics
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / virology
  • Human papillomavirus 16 / pathogenicity
  • Humans
  • Mice
  • Molecular Targeted Therapy*
  • Oncogene Proteins, Viral / genetics
  • Papillomavirus E7 Proteins / genetics
  • Papillomavirus Infections / genetics*
  • Papillomavirus Infections / virology
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Receptor, ErbB-3 / antagonists & inhibitors
  • Receptor, ErbB-3 / genetics*
  • Repressor Proteins / genetics
  • Squamous Cell Carcinoma of Head and Neck
  • Xenograft Model Antitumor Assays

Substances

  • E6 protein, Human papillomavirus type 16
  • Elafin
  • Oncogene Proteins, Viral
  • PI3 protein, human
  • Papillomavirus E7 Proteins
  • RNA, Small Interfering
  • Repressor Proteins
  • ERBB3 protein, human
  • Receptor, ErbB-3