title: High heregulin expression is associated with activated HER3 and may define an actionable biomarker in patients with squamous cell carcinomas of the head and neck.
abstract: OBJECTIVE
  Tumors with oncogenic dependencies on the HER family of receptor tyrosine kinases (RTKs) often respond well to targeted inhibition. Our previous work suggested that many cell lines derived from squamous cell carcinomas of the head and neck (SCCHNs) depend on autocrine signaling driven by HER2/3 dimerization and high-level co-expression of HRG. Additionally, results from a Phase I trial of MEHD7495A, a dual-action antibody that blocks ligand binding to EGFR and HER3, suggest that high-level HRG expression was associated with clinical response in SCCHN patients. Here we explore the hypothesis that high-level HRG expression defines a subpopulation of SCCHNs with activated HER3.
  
  
  METHODS
  qRT-PCR expression profiling was performed on >750 tumors of diverse origin, including >150 therapy-naïve, primary, and recurrent SCCHNs. Activated HER3, defined by immunoprecipitation of phospho-HER3, was compared to HRG expression in SCCHN samples. Paracrine versus autocrine expression was evaluated using RNA-in situ hybridization.
  
  
  RESULTS
  SCCHN tumors express the highest levels of HRG compared to a diverse collection of other tumor types. We show that high HRG expression is associated with activated HER3, whereas low HRG expression is associated with low HER3 activation in SCCHN tumors. Furthermore, HRG expression is higher in recurrent SCCHN compared to patient-matched therapy naïve specimens.
  
  
  CONCLUSIONS
  HRG expression levels define a biologically distinct subset of SCCHN patients. We propose that high-level expression of HRG is associated with constitutive activation of HER3 in SCCHN and thus defines an actionable biomarker for interventions targeting HER3.
authors.affiliation: Oncology Biomarker Development, Genentech Inc., South San Francisco, California, USA. shames.david@gene.com
authors.forename: David S
authors.initials: DS
authors.lastname: Shames
authors.forename: Juliet
authors.initials: J
authors.lastname: Carbon
authors.forename: Kim
authors.initials: K
authors.lastname: Walter
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: Cleopatra
authors.initials: C
authors.lastname: Kozlowski
authors.forename: Tom
authors.initials: T
authors.lastname: Januario
authors.forename: An
authors.initials: A
authors.lastname: Do
authors.lastname: AnDo
authors.forename: Ling
authors.initials: L
authors.lastname: Fu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xiao
authors.forename: Rajiv
authors.initials: R
authors.lastname: Raja
authors.forename: Brittany
authors.initials: B
authors.lastname: Jiang
authors.forename: Ashi
authors.initials: A
authors.lastname: Malekafzali
authors.forename: Howard
authors.initials: H
authors.lastname: Stern
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Wilson
authors.forename: Garret M
authors.initials: GM
authors.lastname: Hampton
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.forename: Andrea
authors.initials: A
authors.lastname: Pirzkall
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Amler
mesh_terms: D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D014408:Biomarkers, Tumor; D020890:Neuregulin-1; D020893:Receptor, ErbB-3