HER2 heterogeneous breast cancer models reveal novel therapeutic targets and subclonal dynamics during evolution to resistance to HER2-targeted therapies - PubMed
5 hours ago
- #preclinical models
- #HER2 heterogeneity
- #breast cancer resistance
- Intratumor HER2 heterogeneity in HER2-positive breast cancer drives resistance to HER2-targeted therapies.
- Novel preclinical models with HER2hi and HER2lo cell populations from the same tumor mimic human HER2 heterogeneous breast cancer.
- HER2lo cells contribute to resistance against antibody-drug conjugates (ADCs) like T-DXd but are sensitive to HER2 kinase inhibitors.
- CRISPR screens in co-cultures identified ABCC1 and USP9X as sensitizers of HER2lo cells to T-DXd.
- Inhibition of USP9X enhances lysosomal targeting of HER2, boosting ADC payload release and reducing tumor recurrence post-T-DXd treatment.