Mode of action of pertuzumab in combination with trastuzumab plus docetaxel therapy in a HER2‑positive breast cancer xenograft model

Yamashita‑Kashima,Yoriko; Shu,Sei; Yorozu,Keigo; Moriya,Yoichiro; Harada,Naoki

doi:10.3892/ol.2017.6679

Mode of action of pertuzumab in combination with trastuzumab plus docetaxel therapy in a HER2‑positive breast cancer xenograft model

Authors:
- Yoriko Yamashita‑Kashima
- Sei Shu
- Keigo Yorozu
- Yoichiro Moriya
- Naoki Harada
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Affiliations: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247‑8530, Japan
Published online on: July 26, 2017 https://doi.org/10.3892/ol.2017.6679
Pages: 4197-4205
Copyright: © Yamashita‑Kashima et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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 in vivo. 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.

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