Therapeutic implication of HER2 in advanced biliary tract cancer.
Therapeutic implication of HER2 in advanced biliary tract cancer.
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DOI：
10.18632/oncotarget.11157
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发表时间：
2016-09-06
期刊：
影响因子：
--
通讯作者：
Bang YJ
中科院分区：
文献类型：
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作者：
Nam AR;Kim JW;Cha Y;Ha H;Park JE;Bang JH;Jin MH;Lee KH;Kim TY;Han SW;Im SA;Kim TY;Oh DY;Bang YJ
目前，对于胆道癌（BTC）还没有有效的治疗靶点。本研究旨在探讨HER2作为BTC治疗靶点的临床前和临床意义。我们从胆囊癌患者身上建立了两个新的her2扩增的BTC细胞系SNU-2670和SNU-2773。与9种her2阴性BTC细胞系相比，SNU-2670和SNU-2773细胞对曲妥珠单抗、达科米替尼和阿法替尼敏感。Dacomitinib和afatinib导致SNU-2773细胞G1周期阻滞和SNU-2670细胞凋亡。此外，dacomitinib、afatinib和曲妥珠单抗与吉西他滨、顺铂、紫杉醇和5-氟尿嘧啶等细胞毒性药物联用时显示协同细胞毒性。在SNU-2670小鼠异种移植模型中，曲妥珠单抗作为单药治疗和与吉西他滨联合治疗显示出良好的抗肿瘤效果，增加细胞凋亡。在我们的临床数据中，13.0%的晚期BTC患者被定义为her2阳性。其中，3名患者完成了her2靶向化疗。其中两名患者表现出部分反应，另一名患者病情稳定了18周。总之，这些临床前和临床数据表明，HER2可能是一种治疗靶点，HER2阳性晚期BTC患者应进一步开发HER2靶向策略。
Currently, there is no validated therapeutic target for biliary tract cancer (BTC). This study aimed to investigate the pre-clinical and clinical implication of HER2 as a therapeutic target in BTC. We established two novel HER2-amplified BTC cell lines, SNU-2670 and SNU-2773, from gallbladder cancer patients. SNU-2670 and SNU-2773 cells were sensitive to trastuzumab, dacomitinib, and afatinib compared with nine HER2-negative BTC cell lines. Dacomitinib and afatinib led to G1 cell cycle arrest in SNU-2773 cells and apoptosis in SNU-2670 cells. Furthermore, dacomitinib, afatinib, and trastuzumab showed synergistic cytotoxicity when combined with some cytotoxic drugs including gemcitabine, cisplatin, paclitaxel, and 5-fluorouracil. In a SNU-2670 mouse xenograft model, trastuzumab demonstrated a good anti-tumor effect as a monotherapy and in combination with gemcitabine increasing apoptosis. In our clinical data, 13.0% of patients with advanced BTC were defined as HER2-positive. Of these, three patients completed HER2-targeted chemotherapy. Two of them demonstrated a partial response, and the other one showed stable disease for 18 weeks. In summary, these pre-clinical and clinical data suggest that HER2 could be a therapeutic target, and that a HER2-targeting strategy should be developed further in patients with HER2-positive advanced BTC.