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. 2016 Sep 28;380(1):20-30.
doi: 10.1016/j.canlet.2016.06.005. Epub 2016 Jun 15.

The anti-HER3 antibody in combination with trastuzumab exerts synergistic antitumor activity in HER2-positive gastric cancer

Qiwei Wang  1 , Xiaotian Zhang  1 , Enyun Shen  2 , Jing Gao  1 , Fengqi Cao  2 , Xiaojuan Wang  1 , Yilin Li  1 , Tiantian Tian  1 , Jingyuan Wang  1 , Zuhua Chen  1 , Jiayuan Wang  1 , Lin Shen  3
Affiliations

The anti-HER3 antibody in combination with trastuzumab exerts synergistic antitumor activity in HER2-positive gastric cancer

Qiwei Wang et al. Cancer Lett. .

Abstract

The anti-HER2 monoclonal antibody trastuzumab is central to the treatment of HER2-positive gastric cancer (GC); however, its responses are limited. HER3 seems to be the preferred dimerization partner with HER2 and is emerging as a key target for complete blockade of downstream pathways and better clinical response. In this study, we report that novel anti-HER3 antibodies (1A5-3D4) that can neutralize multiple modes of HER3 activation, combined with trastuzumab, exhibited synergistic inhibitory effect on the cell proliferation in HER2-positive GC cell lines. Follow-up studies revealed that the combination treatment significantly inhibited phosphorylation of HER3 as well as AKT and ERK signals. In vivo experiments further showed that the anti-tumor effect of trastuzumab was enhanced by its combination with 1A5-3D4 in NCI-N87 xenograft and patient derived xenografts (PDX). Particularly in an HER2-negative whereas neuregulin1 (a ligand of HER3) positive PDX, the combination was also superior to monotherapy. 1A5-3D4 in combination with trastuzumab exhibits a synergistic inhibitory effect on tumor activity, suggesting that targeting both HER2 and HER3 resulted in an improved treatment effects on HER2-positive GC.

Keywords: Anti-HER3 antibodies; Gastric cancer; HER2; HER3; Trastuzumab.

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