Neuregulin 1 expression is a predictive biomarker for response to AV-203, an ERBB3 inhibitory antibody, in human tumor models.

Abstract

PURPOSE:

ERBB3 is overexpressed in a broad spectrum of human cancers, and its aberrant activation is associated with tumor pathogenesis and therapeutic resistance to various anticancer agents. Neuregulin 1 (NRG1) is the predominant ligand for ERBB3 and can promote the heterodimerization of ERBB3 with other ERBB family members, resulting in activation of multiple intracellular signaling pathways. AV-203 is a humanized IgG1/κ ERBB3 inhibitory antibody that completed a first-in-human phase I clinical trial in patients with advanced solid tumors. The purpose of this preclinical study was to identify potential biomarker(s) that may predict response to AV-203 treatment in the clinic.

EXPERIMENTAL DESIGN:

We conducted in vivo efficacy studies using a broad panel of xenograft models representing a wide variety of human cancers. To identify biomarkers that can predict response to AV-203, the relationship between tumor growth inhibition (TGI) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these tumor models.

RESULTS:

A significant correlation was observed between the levels of NRG1 expression and TGI by AV-203. In contrast, TGI was not correlated with ERBB3 expression. The correlation between the levels of NRG1 expression in tumors and their response to ERBB3 inhibition by AV-203 was further validated using patient-derived tumor explant models.

CONCLUSIONS:

NRG1 is a promising biomarker that can predict response to ERBB3 inhibition by AV-203 in preclinical human cancer models. NRG1 warrants further clinical evaluation and validation as a potential predictive biomarker of response to AV-203.

• Authors: Kristan Meetze, Sylvie Vincent, Steven Tyler, Elizabeth K Mazsa, Andrea R Delpero, Steve Bottega, Donna McIntosh, Richard Nicoletti, William M Winston, Solly Weiler, Bin Feng, Jeno Gyuris, Zhigang Weng
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 5 Pg. 1106-14 (Mar 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25542901 (Publication Type: Journal Article)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Biomarkers
• Ligands
• Neuregulin-1
• AV-203
• Receptor, ErbB-3

Topics

• Animals
• Antibodies, Monoclonal, Humanized (administration & dosage, pharmacology)
• Area Under Curve
• Biomarkers
• Cell Line, Tumor
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression
• Humans
• Ligands
• Mice
• Mutation
• Neoplasms (drug therapy, genetics, metabolism, pathology)
• Neuregulin-1 (genetics, metabolism)
• Prognosis
• Protein Binding
• Receptor, ErbB-3 (antagonists & inhibitors, genetics, metabolism)
• Reproducibility of Results
• Xenograft Model Antitumor Assays