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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 5/2020

Open Access 01-11-2020 | Pertuzumab | Original Article

Combination efficacy of pertuzumab and trastuzumab for trastuzumab emtansine-resistant cells exhibiting attenuated lysosomal trafficking or efflux pumps upregulation

Authors: Yoriko Yamashita-Kashima, Sei Shu, Masahiro Osada, Takaaki Fujimura, Shigeki Yoshiura, Naoki Harada, Yasushi Yoshimura

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2020

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Abstract

Purpose

Trastuzumab emtansine (T-DM1) is the standard treatment in the current second-line therapy of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, a useful therapy after T-DM1 resistance has not been established. In this study, we established two different HER2-positive T-DM1-resistant cancer cells and evaluated the antitumor effect of trastuzumab in combination with pertuzumab (TRAS + PER).

Methods

Single-cell-cloned OE19 and BT-474 cells were cultured with increasing concentrations of T-DM1 to generate T-DM1-resistant OE19bTDR and BT-474bTDR cells, respectively. HER2 expression was assessed by immunohistochemistry. Multidrug resistance proteins (MDR1 and MRP1) were evaluated by real-time polymerase chain reaction and western blotting. Intracellular trafficking of T-DM1 was examined by flow cytometry and immunofluorescence staining. Efficacy of TRAS + PER was evaluated by cell proliferation assay, HER3 and AKT phosphorylation, caspase 3/7 activity, and antitumor activity.

Results

HER2 expression of both resistant cells was equivalent to that of the parent cells. Overexpression of MDR1 and MRP1 was observed and affected the T-DM1 sensitivity in the OE19bTDR cells. Abnormal localization of T-DM1 into the lysosomes was observed in the BT-474bTDR cells. In BT-474bTDR cells, TRAS + PER inhibited the phosphorylation of AKT involved in HER2–HER3 signaling, and apoptosis induction and cell proliferation inhibition were significantly higher with TRAS + PER than with the individual drugs. TRAS + PER significantly suppressed tumor growth in the OE19bTDR xenograft model compared with each single agent.

Conclusions

The results suggest that the TRAS + PER combination may be effective in T-DM1-resistant cancer cells where HER2 overexpression is maintained.
Appendix
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Metadata
Title
Combination efficacy of pertuzumab and trastuzumab for trastuzumab emtansine-resistant cells exhibiting attenuated lysosomal trafficking or efflux pumps upregulation
Authors
Yoriko Yamashita-Kashima
Sei Shu
Masahiro Osada
Takaaki Fujimura
Shigeki Yoshiura
Naoki Harada
Yasushi Yoshimura
Publication date
01-11-2020
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 5/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-020-04138-5

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