Xu Wen, Bi Yanyu, Zhang Jiqin, Kong Juan, Jiang Hua, Tian Mi, Li Kesang, Wang Biao, Chen Cheng, Song Fei, Pan Xiaorong, Shi Bizhi, Kong Xianming, Gu Jianren, Cai Xiumei, Li Zonghai
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.
Oncotarget. 2015 Nov 17;6(36):38840-53. doi: 10.18632/oncotarget.6111.
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.
尽管抗HER2抗体曲妥珠单抗可使某些HER2过表达的乳腺癌患者获益，但原发性或获得性曲妥珠单抗耐药仍是一个棘手的问题。在一些乳腺肿瘤中，EGFRvIII与HER2共表达，提示临床预后较差。然而，EGFRvIII在曲妥珠单抗功能中的作用尚不清楚。在此，我们证明EGFRvIII过表达导致原发性曲妥珠单抗耐药，曲妥珠单抗引起的STAT3反馈激活也导致EGFRvIII(+)HER2(+)乳腺癌获得性耐药。CH12是一种高效抗EGFRvIII单克隆抗体，优先结合EGFRvIII，在体外和体内均显著抑制EGFRvIII+HER2(+)乳腺癌细胞的生长。重要的是，CH12与曲妥珠单抗联合在体外和体内对EGFRvIII(+)HER2(+)乳腺癌具有协同抑制作用，可更有效地减弱EGFR和HER2及其下游信号通路的磷酸化，并逆转STAT3反馈激活。此外，联合治疗显著抑制血管生成并诱导细胞凋亡。总之，这些结果提示曲妥珠单抗与CH12联合对EGFRvIII(+)HER2(+)乳腺癌具有协同疗效，这可能是未来潜在的临床应用。
