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

Abstract 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 (BCBM). The scarcity of suitable patient-derived in vivo models for HER2+ BCBM has curtailed the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. Here, we generated and characterized a luminal B HER2+ BCBM cell model (BCBM94) isolated from a patient HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated BCBM 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+ BCBM 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+ BCBM model and identified poziotinib as highly efficacious RTKi with excellent brain penetrability that eliminated HER2+ BCBM.