Trastuzumab Deruxtecan Resistance via Loss of HER2 Expression and Binding.

ABSTRACT: Trastuzumab Deruxtecan (T-DXd) is clinically beneficial in HER2-positive and HER2-low metastatic breast cancer. 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 strat

SUBMITTER: Chen W 

PROVIDER: S-EPMC12631751 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature