{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:36:41Z","timestamp":1787240201216,"version":"build-2736575974"},"reference-count":27,"publisher":"Korean Cancer Association","issue":"2","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/3.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2024-00454656"],"award-info":[{"award-number":["RS-2024-00454656"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["e-crt.org"],"crossmark-restriction":true},"short-container-title":["Cancer Res Treat"],"published-print":{"date-parts":[[2026,4,15]]},"abstract":"<jats:p>Purpose Human epidermal growth factor receptor 2 (HER2) is amplified or overexpressed in various malignancies, including breast and gastric cancers, and is associated with poor prognosis. Although HER2-targeted therapies, such as trastuzumab, improve outcomes in HER2-positive tumors, resistance often develops, and HER2-low tumors remain largely untargeted. Trastuzumab deruxtecan (T-DXd; DS-8201a) is a HER2-targeted antibody-drug conjugate with potent activity in HER2-positive and HER2-low tumors. This study evaluates its antitumor mechanisms and efficacy in HER2-positive, HER2-low, and homologous recombination deficiency (HRD)\u2013associated models.Materials and Methods Effects of T-DXd were assessed in cancer cell lines with diverse HER2 expression and HRD status. In vivo efficacy was evaluated using a xenograft model derived from HER2-low SNU-601 gastric cancer cells.Results T-DXd reduced HER2 phosphorylation and downstream signaling (AKT, ERK) in HER2-positive cells. It induced DNA damage accumulation, as evidenced by increased \u03b3H2AX and p-Chk1 expression, and triggered apoptosis through cleaved poly(ADP-ribose) polymerase and caspase-3 activation, confirmed by annexin V staining. Similar effects were observed in HER2-low cells, with greater sensitivity in HRD cells. In xenografts, T-DXd reduced tumor volume by up to 80% at 4 mg\/kg and 10 mg\/kg. Histological analyses showed decreased Ki-67 and increased apoptosis. Furthermore, T-DXd induced G2\/M cell cycle arrest and nuclear anaplasia, suggesting disruption of chromosomal stability as a potential antitumor mechanism. No significant toxicity, including body weight loss, was observed.Conclusion These findings highlight T-DXd\u2019s effectiveness in HER2-low and HRD tumors, supporting its broader clinical application, including strategies targeting DNA damage repair pathways.<\/jats:p>","DOI":"10.4143\/crt.2025.201","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T07:46:04Z","timestamp":1754293564000},"page":"407-422","update-policy":"https:\/\/doi.org\/10.4143\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["DNA Damage and Nuclear Anaplasia Induced by Trastuzumab Deruxtecan in Cancer Cells with Variable HER2 Expression and Homologous Recombination Deficiency Status"],"prefix":"10.4143","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0809-7907","authenticated-orcid":true,"given":"So 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