Supplementary Table 1. The contingency table for the Fisher’s exact test for xenograft models used in the study. Supplementary Table 2. NRG1 and ERBB3 expression in human cancers from TCGA database. Supplementary Figure 1. Effect of AV-203 on xenograft models in vivo. Supplementary Figure 2. Analysis of NRG1 expression by immunohistochemistry. Supplementary Figure 3. Evaluation of NRG1 and ERBB3 expression in human cancers using TCGA database. Supplementary Figure 4. Correlation analysis between efficacy of AV-203 and the expression levels of ERBB3 (A) or NRG1 (B) in 32 human cancer xenografts included in the study.
ARTICLE 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. Clin Cancer Res; 21(5); 1106–14. ©2014 AACR.
