The anti-ErbB2 antibody H2-18 and the pan-PI3K inhibitor GDC-0941 effectively inhibit trastuzumab-resistant ErbB2-overexpressing breast cancer

// Lingfei Wang 1, 2, * , Xiaojie Yu 2, * , Chao Wang 2, * , Shujun Pan 3, * , Beibei Liang 1 , Yajun Zhang 2 , Xiaodan Chong 2 , Yanchun Meng 4 , Jian Dong 5 , Yirong Zhao 2 , Yang Yang 2 , Huajing Wang 2 , Jie Gao 6 , Huafeng Wei 1, 2 , Jian Zhao 1, 2 , Hao Wang 2 , Chaohua Hu 7 , Wenze Xiao 8 and Bohua Li 1, 2 1 Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China 2 International Joint Cancer Institute, Second Military Medical University, Shanghai 200433, China 3 Hangzhou Sanatorium of People’s Liberation Army, Hangzhou 310007, China 4 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai 200032, China 5 Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China 6 Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China 7 Department of General Surgery, Xiaogan Central Hospital Affiliated to Wuhan University of Science and Technology, Wuhan 432000, China 8 Department of Rheumatology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China * These authors contributed equally to this work Correspondence to: Chaohua Hu, email: huchaohua2006@126.com Wenze Xiao, email: wenzexiao@yahoo.com Bohua Li, email: bohuali1020@163.com Keywords: trastuzumab resistance, GDC-0941, anti-ErbB2 antibody, programmed cell death, breast cancer Received: March 07, 2017      Accepted: May 05, 2017      Published: May 16, 2017 ABSTRACT Trastuzumab, an anti-ErbB2 humanized antibody, brings benefit to patients with ErbB2-amplified metastatic breast cancers. However, the resistance to trastuzumab is common. Our previously reported H2-18, an anti-ErbB2 antibody, potently induced programmed cell death in trastuzumab-resistant breast cancer cells. Here, we aim to investigate the antitumor efficacy of H2-18 in combination with the pan-PI3K inhibitor GDC-0941 in trastuzumab-resistant breast cancer cell lines. The results showed that H2-18 and GDC-0941 synergistically inhibited the in vitro proliferation of BT-474, SKBR-3, HCC-1954 and HCC-1419 breast cancer cells. H2-18 plus GDC-0941 showed significantly enhanced programmed cell death-inducing activity compared with each drug used alone. The combination of H2-18 and GDC-0941 did not increase the effect of single agent on ROS production, cell cycle and ErbB2 signaling. Importantly, the in vivo antitumor efficacy of H2-18 plus GDC-0941 was superior to that of single agent. Thus, the enhanced in vivo antitumor efficacy of H2-18 plus GDC-0941 may mainly be attributable to its increased programmed cell death-inducing activity. Collectively, H2-18 plus GDC-0941 could effectively inhibit tumor growth, suggesting the potential to be translated into clinic as an efficient strategy for ErbB2-overexpressing breast cancers.