Yamashita-Kashima Yoriko, Shu Sei, Yorozu Keigo, Moriya Yoichiro, Harada Naoki
Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
Oncol Lett. 2017 Oct;14(4):4197-4205. doi: 10.3892/ol.2017.6679. Epub 2017 Jul 26.
In a Phase III trial for HER2-positive breast cancer (the CLEOPATRA study), the triple-drug combination arm of pertuzumab plus trastuzumab plus docetaxel showed significantly longer progression-free survival and overall survival than did the trastuzumab plus docetaxel arm. In this study, we investigated the mechanism of action of the triple-drug combination therapy . For this purpose, we established a mouse xenograft model using KPL-4, a HER2-positive human breast cancer cell line, in which the triple-drug combination treatment dramatically induced tumor regression compared with double-drug combinations (trastuzumab plus docetaxel, pertuzumab plus docetaxel, or pertuzumab plus trastuzumab). Four days after the triple-drug treatment was started, strong reduction in the phosphorylation of HER2, epidermal growth factor receptor (EGFR), HER3, extracellular signal-regulated kinase (ERK), and AKT in tumor tissues was seen, despite only weak suppression of phosphorylation seen with the single- or double-drug treatments. Histopathological analysis and flow cytometric analysis showed that the triple-drug treatment enhanced apoptosis after mitotic arrest induced by docetaxel. Furthermore, infiltration of mononuclear cells around the tumor cells was strongly induced by the triple-drug combination treatment. These results suggested that the mechanism underlying the synergistic efficacy of the triple-drug combination was attributable, at least in part, to the docetaxel-mediated apoptosis being promoted by enhanced inhibition of HER2-HER3-AKT signaling as well to the intratumor infiltration of mononuclear cells induced by anti-HER2 antibodies being enhanced by docetaxel.
在一项针对HER2阳性乳腺癌的III期试验（CLEOPATRA研究）中，帕妥珠单抗联合曲妥珠单抗加多西他赛的三联药物组合组比曲妥珠单抗加多西他赛组显示出显著更长的无进展生存期和总生存期。在本研究中，我们探究了三联药物联合疗法的作用机制。为此，我们使用KPL-4（一种HER2阳性人乳腺癌细胞系）建立了小鼠异种移植模型，与双联药物组合（曲妥珠单抗加多西他赛、帕妥珠单抗加多西他赛或帕妥珠单抗加曲妥珠单抗）相比，三联药物联合治疗显著诱导了肿瘤消退。三联药物治疗开始四天后，尽管单药或双药治疗仅对磷酸化有微弱抑制，但肿瘤组织中HER2、表皮生长因子受体（EGFR）、HER3、细胞外信号调节激酶（ERK）和AKT的磷酸化水平显著降低。组织病理学分析和流式细胞术分析表明，三联药物治疗增强了多西他赛诱导的有丝分裂停滞后的细胞凋亡。此外，三联药物联合治疗强烈诱导了肿瘤细胞周围单核细胞的浸润。这些结果表明，三联药物联合协同疗效的机制至少部分归因于多西他赛介导的细胞凋亡通过增强对HER2-HER3-AKT信号通路的抑制而得到促进，以及抗HER2抗体诱导的肿瘤内单核细胞浸润通过多西他赛而增强。
