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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\u2009+\u2009PER).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>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\u2009+\u2009PER was evaluated by cell proliferation assay, HER3 and AKT phosphorylation, caspase 3\/7 activity, and antitumor activity.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>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\u2009+\u2009PER inhibited the phosphorylation of AKT involved in HER2\u2013HER3 signaling, and apoptosis induction and cell proliferation inhibition were significantly higher with TRAS\u2009+\u2009PER than with the individual drugs. TRAS\u2009+\u2009PER significantly suppressed tumor growth in the OE19bTDR xenograft model compared with each single agent.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The results suggest that the TRAS\u2009+\u2009PER combination may be effective in T-DM1-resistant cancer cells where HER2 overexpression is maintained.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00280-020-04138-5","type":"journal-article","created":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T07:03:56Z","timestamp":1601449436000},"page":"641-654","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Combination efficacy of pertuzumab and trastuzumab for trastuzumab emtansine-resistant cells exhibiting attenuated lysosomal trafficking or efflux pumps upregulation"],"prefix":"10.1007","volume":"86","author":[{"given":"Yoriko","family":"Yamashita-Kashima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sei","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Osada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Fujimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeki","family":"Yoshiura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1468-0636","authenticated-orcid":false,"given":"Naoki","family":"Harada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Yoshimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,30]]},"reference":[{"key":"4138_CR1","doi-asserted-by":"publisher","first-page":"9280","DOI":"10.1158\/0008-5472.CAN-08-1776","volume":"68","author":"GD Lewis Phillips","year":"2008","unstructured":"Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Bl\u00e4ttler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. 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This article does not contain any evaluations on human participants. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (the Institutional Animal Care and Use Committee at Chugai Pharmaceutical, Co., Ltd., No. 15-362).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}