Modeling of De Novo Resistance to Trastuzumab Deruxtecan in HER2-Positive Patient-Derived Xenografts

Resistance to trastuzumab deruxtecan (T-DXd) in HER2-positive cancers represents a significant unmet clinical need. GemPharmatech has established a patient-derived xenograft (PDX) model of intrinsic T-DXd resistance derived from lung and gastric cancers. This model maintains high HER2 expression yet demonstrates robust resistance to T-DXd in vivo. The persistence of HER2 without target loss strongly suggests alternative resistance mechanisms independent of antigen downregulation. This clinically relevant PDX model provides a valuable platform for dissecting T-DXd resistance biology, identifying predictive biomarkers, and evaluating novel therapeutic strategies or combinations for HER2-positive tumors.