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However, therapeutic resistance emerges over time in most patients, with poorly defined resistance mechanisms. Through a molecular characterization of paired patient specimens before and after T-DXd treatment, we found that 49% cases had major decreases in HER2 expression at progression, and among them, 52% exhibited complete HER2 loss. Using isogenic model systems, we demonstrated that decreases in HER2 expression corresponded to reductions in T-DXd internalization and major increases in drug IC50 value for tumor growth inhibition. We further identified and validated ERBB2 mutations in the trastuzumab binding interface (V597M and P593R) that promoted T-DXd resistance. As a strategy to overcome impaired T-DXd binding and internalization, we tested low-dose combinations of T-DXd with TROP2-directed antibody\u2013drug conjugates (ADC) and found that these could more uniformly deliver DXd payloads and thereby overcome resistance mediated by HER2 loss.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>The mechanisms underlying clinical T-DXd resistance have not been established. We now report on two mechanisms of resistance that converge on loss of target binding and propose combinations of distinct ADCs with shared payloads as a strategy to overcome resistance by enhancing intratumor delivery.<\/jats:p>\n                    <jats:p>See related commentary by O\u2019Meara and Tarantino, p.195<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0647","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T15:26:53Z","timestamp":1762788413000},"page":"235-249","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Trastuzumab Deruxtecan Resistance via Loss of HER2 Expression and Binding"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0876-4203","authenticated-orcid":false,"given":"Wanyi","family":"Chen","sequence":"first","affiliation":[{"name":"1Human Oncology and Pathogenesis Program, Memorial Sloan 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