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Purpose  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.    Experimental Design  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.

plos one

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