Researchers have identified a key mechanism behind drug resistance in some HER2-positive breast cancers treated with antibody-drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd). The culprit is p95HER2, a truncated form of HER2 that alters cellular signaling and creates an immune-protected tumor microenvironment, preventing ADCs from effectively killing cancer cells.
Preclinical studies showed that neratinib, a pan-HER tyrosine kinase inhibitor, can degrade p95HER2, potentially restoring sensitivity to T-DXd. This suggests a new therapeutic strategy: combining neratinib with T-DXd to overcome resistance in tumors expressing p95HER2.
Clinical trials are being planned to test the safety and efficacy of this combination. This discovery not only explains why some HER2-positive tumors fail current therapies but also offers a path toward personalized treatment, representing a major advance in addressing drug resistance in breast cancer.