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

// Chao Wang 1, * , Lingfei Wang 1, * , Xiaojie Yu 1, * , Yajun Zhang 1, * , Yanchun Meng 2 , Huajing Wang 1 , Yang Yang 1 , Jie Gao 1 , Huafeng Wei 1, 3 , Jian Zhao 1, 3 , Cuihua Lu 4 , Han Chen 5 , Yanping Sun 6 and Bohua Li 1, 3 1 International Joint Cancer Institute and Department of Pharmaceutical Sciences, The Second Military Medical University, Shanghai, People's Republic of China 2 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China 3 Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, People’s Republic of China 4 Department of Gastroenterology, The Affiliated Hospital of Nantong University, Nantong, People’s Republic of China 5 Department of General Surgery, 411 Hospital of Chinese People's Liberation Army, Shanghai, People’s Republic of China 6 Department 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.