title: Synergistic antitumor efficacy against the EGFRvIII+HER2+ breast cancers by combining trastuzumab with anti-EGFRvIII antibody CH12.
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.
authors.affiliation: Medical School of Fudan University, Shanghai, China.|State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Wen
authors.initials: W
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Yanyu
authors.initials: Y
authors.lastname: Bi
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Jiqin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Juan
authors.initials: J
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Mi
authors.initials: M
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Kesang
authors.initials: K
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Biao
authors.initials: B
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Bizhi
authors.initials: B
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Xianming
authors.initials: X
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Jianren
authors.initials: J
authors.lastname: Gu
authors.affiliation: Medical School of Fudan University, Shanghai, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai,China.
authors.forename: Zonghai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000096:biosynthesis / Q000276:immunology*; D005260:Female; D006801:Humans; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000068878:Trastuzumab / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D000068878:Trastuzumab; C585627:CH12 monoclonal antibody; C494086:STAT3 protein, human; C410723:epidermal growth factor receptor VIII; C508053:ERBB2 protein, human
keywords: CH12; EGFRvIII; EGFRvIII+HER2+ breast cancers; STAT3; trastuzumab resistance