{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:59:39Z","timestamp":1790827179777,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T00:00:00Z","timestamp":1768608000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T00:00:00Z","timestamp":1768608000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K27609"],"award-info":[{"award-number":["23K27609"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Antibody\u2013drug conjugates (ADCs) are emerging as a promising class of targeted cancer therapy. Trastuzumab deruxtecan (T\u2010DXd), a human epidermal growth factor receptor 2 (HER2)\u2010directed ADC, has demonstrated clinical efficacy in HER2\u2010positive gastric and breast cancers, as well as in HER2\u2010mutant non\u2010small cell lung cancer. However, the development of acquired resistance limits their long\u2010term efficacy. To elucidate the resistance mechanism, we established T\u2010DXd\u2010resistant cell lines derived from HER2\u2010amplified gastric xenografts (N87 acquired resistance [AR]) and leptomeningeal carcinomatosis (Calu\u20103 AR) lung cancer cells. N87 AR cells exhibited cross\u2010resistance to T\u2010DXd, payload DXd, and topoisomerase I inhibitor SN\u201038 despite preserved HER2 expression and intact drug internalization. As payload resistance\u2010related molecules, ATP\u2010binding cassette (ABC) transporter ABCG2 and ABCB1 were markedly upregulated in N87 AR and Calu\u20103 cells, respectively. Inhibition of ABCG2 and ABCB1 in N87 AR and Calu\u20103 cells, respectively, through siRNA\u2010mediated knockdown restored T\u2010DXd sensitivity in both models. As a strategy to overcome resistance, pharmacological inhibitors of ABCG2 and ABCB1 restored the T\u2010DXd sensitivity of N87 AR and Calu\u20103 cells, respectively. Moreover, BB\u20101701, a novel HER2\u2010ADC containing eribulin as a payload, to which N87 AR cells are sensitive, exhibited antitumor effects in N87 AR cells in\u00a0vitro and in\u00a0vivo. These findings indicate that ABC transporter\u2010mediated drug efflux is an important mechanism underlying T\u2010DXd resistance in HER2\u2010positive gastric and lung cancer models. Furthermore, our study suggests that both targeting drug efflux pathways and utilizing alternative payloads may be effective strategies for overcoming T\u2010DXd resistance in HER2\u2010positive gastric and lung cancers.<\/jats:p>","DOI":"10.1111\/cas.70319","type":"journal-article","created":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T07:25:47Z","timestamp":1768721147000},"page":"996-1009","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Therapeutic Strategies to Overcome Payload Resistance of Trastuzumab Deruxtecan in\n                    <scp>HER2<\/scp>\n                    \u2010Positive Cancers"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6328-4174","authenticated-orcid":false,"given":"Yuya","family":"Murase","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine Kanazawa University Hospital  Kanazawa Ishikawa 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