The Brain-Penetrant Pan-ErbB Inhibitor Poziotinib Effectively Targets HER2⁺ Breast Cancer Brain Metastases

Brain metastasis occurs in about 50% of all women with metastatic HER2⁺ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2⁺ breast cancer with trastuzumab and HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2⁺ breast cancer brain metastasis. The scarcity of suitable patient-derived in vivo models for HER2⁺ breast cancer brain metastasis has curtailed the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. In this study, we generated and characterized a luminal B HER2⁺ breast cancer brain metastasis cell model (BCBM94) isolated from a patient with HER2⁺ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated breast cancer brain metastasis in mice. The clinical receptor tyrosine kinase inhibitor (RTKi) lapatinib blocked phosphorylation of all ERBB receptors (ERBB1–4) and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin 1 (Nrg1), an ERBB3/ ERBB4 ligand that is abundantly expressed in the brain, abrogated lapatinib-induced apoptosis in HER2⁺ BCBM94 and BT474 models. ErbB3 signaling pathways that involved PI3K–AKT and the phosphorylation of BAD at serine 136 to prevent apoptosis were essential for Nrg1-induced survival. High-throughput RTKi screening identified the brain-penetrant pan-ErbB inhibitor poziotinib as a highly potent compound that reduced cell viability in HER2⁺ breast cancer brain metastasis in the presence of NRG1. Two weeks of poziotinib treatment successfully ablated BCBM94 and BT474 HER2⁺ brain tumors in vivo. In conclusion, this study established a patient-derived HER2⁺ breast cancer brain metastasis model and identified poziotinib as a highly efficacious RTKi with excellent brain penetrability that eliminated HER2⁺ breast cancer brain metastasis.(Figure