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.
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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)
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Copyright | ©2014 American Association for Cancer Research. |
Chemical References |
- Antibodies, Monoclonal, Humanized
- Biomarkers
- Ligands
- Neuregulin-1
- AV-203
- Receptor, ErbB-3
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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
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