title: Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+Patients.
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.
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.
authors.forename: Toni M
authors.initials: TM
authors.lastname: Brand
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.|Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bhola
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.
authors.forename: Noah D
authors.initials: ND
authors.lastname: Peyser
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, California.
authors.forename: Erin
authors.initials: E
authors.lastname: Isaacson Wechsler
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Max V
authors.initials: MV
authors.lastname: Ranall
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Sourav
authors.initials: S
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Umamaheswar
authors.initials: U
authors.lastname: Duvvuri
authors.affiliation: Kolltan Pharmaceuticals, New Haven, Connecticut.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: LaVallee
authors.affiliation: Departments of Orofacial Sciences and Pathology, University of California San Francisco, San Francisco, California.
authors.forename: Richard C K
authors.initials: RCK
authors.lastname: Jordan
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Johnson
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California. jennifer.grandis@ucsf.edu.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D053492:Elafin / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology; D052162:Human papillomavirus 16 / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009856:Oncogene Proteins, Viral / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics* / Q000821:virology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D053492:Elafin; D009856:Oncogene Proteins, Viral; C506806:PI3 protein, human; D050725:Papillomavirus E7 Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3