Han Siqi, Meng Yanchun, Tong Qing, Li Guangchao, Zhang Xunmin, Chen Yalin, Hu Shi, Zheng Lei, Tan Wenlong, Li Hui, Chen Yang, Zhang Ge, Li Bohua, Guo Yajun
PLA General Hospital Cancer Center; PLA Postgraduate School of Medicine; Beijing, People's Republic of China; College of Pharmacy; Liaocheng University; Liaocheng, People's Republic of China.
School of Medicine; Nankai University; Tianjin, People's Republic of China; College of Pharmacy; Liaocheng University; Liaocheng, People's Republic of China.
MAbs. 2014 Mar-Apr;6(2):403-8. doi: 10.4161/mabs.27443. Epub 2013 Dec 9.
The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in ErbB2-overexpressing breast and gastric cancer, but resistance to the drug is common. Here, we investigated the antitumor activity of the combination of trastuzumab and the SRC inhibitor saracatinib in ErbB2-overexpressing trastuzumab-resistant gastric cancer. The ErbB2-overexpressing human gastric cancer cell line NCI-N87 was treated with trastuzumab to obtain the trastuzumab-resistant cell line NCI-N87R. The NCI-N87R cell line showed a marked increase in SRC activity and ErbB signaling compared with the NCI-N87 cell line. Our data demonstrated that trastuzumab plus saracatinib was much more potent than either agent alone in reducing the phosphorylation of ErbB3 and AKT in both NCI-N87 and NCI-N87R gastric cancer cell lines. Trastuzumab and saracatinib synergistically inhibited the in vitro growth of NCI-N87 and NCI-N87R cell lines. Further data showed that combination therapy of trastuzumab with saracatinib resulted in a significant benefit over either agent alone in both NCI-N87 and NCI-N87R xenograft models, suggesting its potential use for treating ErbB2-overexpressing gastric cancer.
抗ErbB2抗体曲妥珠单抗已在ErbB2过表达的乳腺癌和胃癌中显示出显著的临床益处，但对该药物产生耐药性很常见。在此，我们研究了曲妥珠单抗与SRC抑制剂萨拉卡替尼联合应用于ErbB2过表达的曲妥珠单抗耐药性胃癌的抗肿瘤活性。用曲妥珠单抗处理过表达ErbB2的人胃癌细胞系NCI-N87，以获得曲妥珠单抗耐药细胞系NCI-N87R。与NCI-N87细胞系相比，NCI-N87R细胞系的SRC活性和ErbB信号传导显著增加。我们的数据表明，在NCI-N87和NCI-N87R胃癌细胞系中，曲妥珠单抗加萨拉卡替尼在降低ErbB3和AKT磷酸化方面比单独使用任何一种药物都更有效。曲妥珠单抗和萨拉卡替尼协同抑制NCI-N87和NCI-N87R细胞系的体外生长。进一步的数据表明，在NCI-N87和NCI-N87R异种移植模型中，曲妥珠单抗与萨拉卡替尼联合治疗比单独使用任何一种药物都产生了显著的益处，表明其在治疗ErbB2过表达胃癌方面的潜在用途。
