Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
J Gastroenterol. 2015 Apr;50(4):467-79. doi: 10.1007/s00535-014-0984-5. Epub 2014 Aug 12.
Pertuzumab is a humanized monoclonal antibody that binds to HER2 at an epitope that prevents HER2 from dimerizing with ligand-activated HER-family receptors. To assess the potential of pertuzumab as a new therapy, the expression status of HER family members was determined in biliary tract carcinoma (BTC), and the antitumor activity of pertuzumab was investigated by assessing the inhibition of BTC cell growth.
The expression status of HER family members in 113 archival specimens of BTC was analyzed by using immunohistochemistry and fluorescence in situ hybridization. Using ten BTC cell lines, heregulin-alpha (HRG-α) stimulated cell proliferation and its inhibition by pertuzumab was tested in vitro. The phosphorylated HER family proteins and their respective downstream molecules were analyzed. In vivo antitumor activity of pertuzumab was evaluated in a xenograft model.
Protein overexpression of HER2 and/or HER3 was observed in 23-34 % of the specimens and gene amplification in 17-27 %. Seven of the ten cell lines showed HER2 and/or HER3 protein overexpression and gene amplification, and HRG-α stimulated cell proliferation was observed in four of the ten cell lines. In a BTC cell line co-overexpressing HER2 and HER3, pertuzumab potently inhibited the HRG-α stimulated cell proliferation in a dose-dependent manner, and completely blocked the phosphorylation of HER3. Suppression of downstream pathway molecules including p-AKT was also observed. Pertuzumab inhibited the in vivo growth of subcutaneous tumors, and increased the number of apoptotic cancer cells.
Pertuzumab exerts potent antitumor activity in BTC cells co-overexpressing HER2 and HER3. Pertuzumab provides a new therapeutic option against BTC.
帕妥珠单抗是一种人源化单克隆抗体，可与 HER2 结合在一个表位上，阻止 HER2 与配体激活的 HER 家族受体二聚化。为了评估帕妥珠单抗作为一种新疗法的潜力，我们通过评估对 BTC 细胞生长的抑制作用，检测了 HER 家族成员在胆道癌 (BTC) 中的表达状态，并研究了帕妥珠单抗的抗肿瘤活性。
使用免疫组织化学和荧光原位杂交分析了 113 份 BTC 存档标本中 HER 家族成员的表达状态。在十种 BTC 细胞系中，我们测试了 HRG-α 刺激细胞增殖及其对帕妥珠单抗的抑制作用。分析了磷酸化的 HER 家族蛋白及其各自的下游分子。在异种移植模型中评估了帕妥珠单抗的体内抗肿瘤活性。
在 23-34%的标本中观察到 HER2 和/或 HER3 蛋白过表达，在 17-27%的标本中观察到基因扩增。十种细胞系中有七种显示 HER2 和/或 HER3 蛋白过表达和基因扩增，其中四种细胞系观察到 HRG-α 刺激细胞增殖。在共过表达 HER2 和 HER3 的 BTC 细胞系中，帕妥珠单抗以剂量依赖性方式强烈抑制 HRG-α 刺激的细胞增殖，并完全阻断 HER3 的磷酸化。还观察到下游通路分子如 p-AKT 的抑制。帕妥珠单抗抑制了皮下肿瘤的体内生长，并增加了凋亡癌细胞的数量。
帕妥珠单抗在共过表达 HER2 和 HER3 的 BTC 细胞中发挥强大的抗肿瘤活性。帕妥珠单抗为 BTC 提供了一种新的治疗选择。
