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

PurposeTumors 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 DesignqRT-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.ResultsSCCHN 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.

First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors

“…One patient with a triple-negative breast cancer showed a dramatic reduction of tumor load at 1,600 mg of lumretuzumab. Assessment of baseline tumor characteristics in this patient revealed highly elevated expression levels of heregulin mRNA and pHER3 and pAkt protein expression, indicating a highly activated HER3 pathway or HER3/heregulin autocrine loop as described previously in head and neck, ovarian and breast cancer tumors/cell lines (14,16,28). None of the other tumors analyzed in this trial showed similar baseline biomarker features, indicating that HER3 pathway activation may be correlated to response to HER3-targeted therapy and that heregulin gene expression may be a clinically measurable surrogate for HER3 pathway activation and a predictive biomarker.…”

“…Nevertheless, it may be worth enriching the study population for tumor subtypes in which heregulin expression has been demonstrated to be elevated. Shames and colleagues (16) reported that heregulin expression was increased in a proportion of patients with head and neck cancer. Others have found heregulin to be highly expressed in BRAF-mutated thyroid cancer cells (33).…”

“…HER3 expression has been described as an adverse prognostic factor in many tumor types including breast, lung, ovarian, and colon cancers (7)(8)(9)(10)(11). In addition, autocrine loops involving the ligand heregulin and leading to HER3 activation have been described in head and neck, lung and ovarian cancer (8,(12)(13)(14)(15)(16).…”

MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors

“…However, recently, a close association between IGF-IR and the ErbB pathway was discovered by multiple investigators: ErbB2, ErbB3, and IGF-IR trimers conferred resistance to trastuzumab in breast cancer cell lines (25); IGF-IR/Insulin receptor inhibition was shown to increase ErbB3 phosphorylation in multiple hepatoma cell lines (26); inhibition of IGF-IR resensitized non-small cell lung cancer (NSCLC) cells to erlotinib (27); and, addition of exogenous heregulin (HRG), the ligand partner for ErbB3, reduced the antiproliferative effects of anti-IGF-IR/Insulin receptor treatment in MCF7 cells overexpressing ErbB2 (28). HRG-ErbB3 autocrine loops have been found to preexist in ovarian cancer cells (29) and squamous cell carcinomas of the head and neck (30), and are inducible in de novo lung cancer models through EGFR inhibition with cetuximab (31). ErbB3 is known to be a key driver of PI3K/AKT/mTOR signaling (32), the inhibition of which is also the intended effect of anti-IGF-IR therapies.…”

Neuregulin 1 Expression Is a Predictive Biomarker for Response to AV-203, an ERBB3 Inhibitory Antibody, in Human Tumor Models

“…An activated NRG1/ERBB3 autocrine signaling loop was found to be critical for the proliferation of ovarian cancer cells in vivo (45). High NRG1 expression was found to be associated with activated ERBB3 in SCCHN and was proposed as an actionable biomarker in patients with SCCHN (46). Recently, a retrospective analysis of a phase II study involving an ERBB3 inhibitory mAb, patritumab, in combination with erlotinib in advanced NSCLCs also identified NRG1 as a potential response biomarker to ERBB3-targeted therapies (47), further validating our preclinical findings.…”