Combination efficacy of pertuzumab and trastuzumab for trastuzumab emtansine-resistant cells exhibiting attenuated lysos
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ORIGINAL ARTICLE
Combination efficacy of pertuzumab and trastuzumab for trastuzumab emtansine‑resistant cells exhibiting attenuated lysosomal trafficking or efflux pumps upregulation Yoriko Yamashita‑Kashima1 · Sei Shu1 · Masahiro Osada1 · Takaaki Fujimura1 · Shigeki Yoshiura1 · Naoki Harada1 · Yasushi Yoshimura1 Received: 16 March 2020 / Accepted: 4 September 2020 © The Author(s) 2020
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. Keywords Pertuzumab · Trastuzumab · Trastuzumab emtansine · T-DM1 resistance · HER2 Abbreviations ABC ATP-binding cassette ABCB1 ATP-binding cassette subfamily B member 1 ABCC1 ATP-binding cassette subfamily C member 1 ADCC Antibody-dependent cellular cytotoxicity ATP Adenosine triphosphate Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04138-5) contains supplementary material, which is available to authorized users. * Naoki Harada haradanok@chugai‑pharm.co.jp 1
Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247‑8530, Japan
BCRP Breast cancer resistance protein CAPE Capecitabine CDC20 Cell-division cycle protein 20 CDK1 Cyclin-dependent kinase 1 EGFR Epidermal growth factor receptor HER2 Human epidermal grow
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