Oncotarget

Research Papers:

Combating acquired resistance to trastuzumab by an anti-ErbB2 fully human antibody

Chao Wang, Lingfei Wang, Xiaojie Yu, Yajun Zhang, Yanchun Meng, Huajing Wang, Yang Yang, Jie Gao, Huafeng Wei, Jian Zhao, Cuihua Lu, Han Chen, Yanping Sun and Bohua Li _

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Oncotarget. 2017; 8:42742-42751. https://doi.org/10.18632/oncotarget.17451

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Abstract

Chao Wang1,*, Lingfei Wang1,*, Xiaojie Yu1,*, Yajun Zhang1,*, Yanchun Meng2, Huajing Wang1, Yang Yang1, Jie Gao1, Huafeng Wei1,3, Jian Zhao1,3, Cuihua Lu4, Han Chen5, Yanping Sun6 and Bohua Li1,3

1International Joint Cancer Institute and Department of Pharmaceutical Sciences, The Second Military Medical University, Shanghai, People's Republic of China

2Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China

3Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, People’s Republic of China

4Department of Gastroenterology, The Affiliated Hospital of Nantong University, Nantong, People’s Republic of China

5Department of General Surgery, 411 Hospital of Chinese People's Liberation Army, Shanghai, People’s Republic of China

6Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Correspondence to:

Bohua Li, email: bohuali1020@163.com

Yanping Sun, email: sunyanping2003@163.com

Han Chen, email: chenhan0903@163.com

Cuihua Lu, email: lch670608@sina.com

Keywords: ErbB2, gastric cancer, acquired resistance to trastuzumab, domain I- specific antibody, programmed cell death

Received: December 16, 2016     Accepted: April 12, 2017     Published: April 27, 2017

ABSTRACT

Trastuzumab resistance is a common problem that impedes the effectiveness of trastuzumab in ErbB2-amplified cancers. About 70% of ErbB2-amplified breast cancers do not respond to trastuzumab (de novo resistance), and the majority of the trastuzumab-responsive cancers progress within 1 year (acquired resistance). Different mechanisms exist between de novo and acquired resistance. Innate resistance mechanisms are mainly independent of ErbB2 receptor activity, and acquired resistance involves with alterations depending on ErbB2 activity. We previously reported H2-18, an ErbB2 domain I-specific antibody, which could circumvent de novo resistance to trastuzumab. Here, we modeled the development of acquired resistance by treating human gastric cancer cell line NCI-N87 with trastuzumab to obtain the trastuzumab-resistant subline, NCI-N87-TraRT. Next, we investigated the antitumor efficacy of H2-18 in NCI-N87-TraRT cell line. H2-18 exhibited a significantly greater antitumor activity in NCI-N87-TraRT tumor-bearing nude mice than pertuzumab and trastuzumab, either alone or in combination. The unique ability of H2-18 to overcome acquired resistance may be attributable to its potent programmed cell death-inducing activity, which was probably mediated by RIP1-ROS-JNK-c-Jun pathway. In conclusion, H2-18 may have the potential as an effective agent to circumvent acquired resistance to trastuzumab in ErbB2-overexpressing cancers.


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