Oncotarget

Research Papers:

Synergistic antitumor efficacy against the EGFRvIII+HER2+ breast cancers by combining trastuzumab with anti-EGFRvIII antibody CH12

Wen Xu, Yanyu Bi, Jiqin Zhang, Juan Kong, Hua Jiang, Mi Tian, Kesang Li, Biao Wang, Cheng Chen, Fei Song, Xiaorong Pan, Bizhi Shi, Xianming Kong, Jianren Gu, Xiumei Cai and Zonghai Li _

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Oncotarget. 2015; 6:38840-38853. https://doi.org/10.18632/oncotarget.6111

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Abstract

Wen Xu1,2,*, Yanyu Bi2,*, Jiqin Zhang2, Juan Kong2, Hua Jiang2, Mi Tian2, Kesang Li2, Biao Wang2, Cheng Chen2, Fei Song2, Xiaorong Pan2, Bizhi Shi2, Xianming Kong2, Jianren Gu2, Xiumei Cai1 and Zonghai Li2

1 Medical School of Fudan University, Shanghai, China

2 State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China

* These authors have contributed equally to this article

Correspondence to:

Zonghai Li, email:

Xiumei Cai, email:

Keywords: EGFRvIII+HER2+ breast cancers, EGFRvIII, CH12, trastuzumab resistance, STAT3

Received: June 10, 2015 Accepted: September 17, 2015 Published: October 14, 2015

Abstract

Although Trastuzumab, an anti-HER2 antibody, benefits certain patients with HER2-overexpressing breast cancer, de novo or acquired trastuzumab resistance remains a haunting issue. EGFRvIII, co-expressing with HER2 in some breast tumors, indicates a poor clinical prognosis. However, the role of EGFRvIII in the function of trastuzumab is not clear. Here, we demonstrated that EGFRvIII overexpression contributed to de novo trastuzumab resistance and the feedback activation of STAT3 caused by trastuzumab also resulted in acquired resistance in EGFRvIII+HER2+ breast cancers. CH12, a highly effective anti-EGFRvIII monoclonal antibody that preferentially binds to EGFRvIII, significantly suppressed the growth of EGFRvIII+HER2+ breast cancer cells in vitro and in vivo. Importantly, CH12 in combination with trastuzumab had a synergistic inhibitory effect on EGFRvIII+HER2+ breast cancers in vitro and in vivo via attenuating the phosphorylation of EGFR and HER2 and their downstream signal pathways more effectively and reversing STAT3 feedback activation. Moreover, the combination therapy suppressed angiogenesis and induced cell apoptosis significantly. Together, these results suggested a synergistic efficacy of the combination of trastuzumab with CH12 against EGFRvIII+HER2+ breast cancers, which might be a potential clinical application in the future.


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