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

  • Oncotarget. 2017 May 16;8(32):52877-52888. doi: 10.18632/oncotarget.17907.
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 ,  Bohua Li  1  2
Affiliations
  • 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.
  • # Contributed equally.
PMID: 28881779 DOI: 10.18632/oncotarget.17907
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.

Keywords
GDC-0941; anti-ErbB2 antibody; breast cancer; programmed cell death; trastuzumab resistance.
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