{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T01:57:34Z","timestamp":1780451854673,"version":"3.54.1"},"reference-count":39,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017346","name":"Nippon Boehringer Ingelheim Co., Ltd.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017346","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Trastuzumab deruxtecan (T-DXd), an antibody\u2013drug conjugate comprising trastuzumab linked to a payload DXd, has been extensively used to treat various cancers harboring HER2 overexpression. However, resistance development has been a major challenge to T-DXd treatment. To explore treatment strategies for T-DXd-resistant cancers, we examined two T-DXd-resistant cells named DSR32 and DSR4, which were obtained from HER2 gene-amplified H2170 lung cancer and N87 gastric cancer cells, respectively. The uptake of T-DXd and its transport to lysosomes in DSR32 cells were reduced. Subsequently, HER2 gene copy number (from 54 to 12) was reduced, which decreased HER2 expression on the cell surface. Thus, T-DXd-resistance might be observed due to the reduced T-DXd uptake caused by decreased HER2 expression in DSR32 cells. In DSR4 cells, no change was observed in HER2 expression and in the uptake and transport of T-DXd. The reduced linker cleavage activity may be associated with T-DXd resistance in DSR4 cells. Meanwhile, both DSR32 and DSR4 cells maintained HER2 activation; thus, zongertinib, a HER2-selective tyrosine kinase inhibitor, blocked the HER2 pathway, induced apoptosis, and inhibited colony formation. Overall, zongertinib can provide therapeutic relief to patients with HER2-overexpressing cancer who have developed resistance to T-DXd.<\/jats:p>","DOI":"10.3390\/ijms262110515","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T17:38:22Z","timestamp":1761759502000},"page":"10515","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Zongertinib, a Novel HER2 Tyrosine Kinase Inhibitor, Maintains an Anticancer Activity for Trastuzumab Deruxtecan-Resistant Cancers Harboring HER2-Overexpression"],"prefix":"10.3390","volume":"26","author":[{"given":"Takashi","family":"Kurosaki","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Kindai University Faculty of Medicine, Sakai 590-0197, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3870-2214","authenticated-orcid":false,"given":"Shinichiro","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kindai University Faculty of Medicine, Sakai 590-0197, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimio","family":"Yonesaka","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kindai University Faculty of Medicine, Sakai 590-0197, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Kawanaka","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kindai University Faculty of Medicine, Sakai 590-0197, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyuki","family":"Takehara","sequence":"additional","affiliation":[{"name":"Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University Faculty of Medicine, Sakai 590-0197, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Teramura","sequence":"additional","affiliation":[{"name":"Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University Faculty of Medicine, Sakai 590-0197, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuko","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Genome Biology, Kindai University Faculty of Medicine, Sakai 590-0197, Japan"},{"name":"Center for Genomics, Life Science Research Institute, Kindai University, Sakai 590-0197, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8275-0846","authenticated-orcid":false,"given":"Kazuto","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Genome Biology, Kindai University Faculty of Medicine, Sakai 590-0197, Japan"},{"name":"Center for Genomics, Life Science Research Institute, Kindai University, Sakai 590-0197, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8787-5587","authenticated-orcid":false,"given":"Hidetoshi","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kindai University Faculty of Medicine, Sakai 590-0197, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1093\/annonc\/12.suppl_1.S3","article-title":"The basic biology of HER2","volume":"12","author":"Rubin","year":"2001","journal-title":"Ann. 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