PRCA-11 ENDOTHELIN RECEPTOR ANTAGONISTS ENHANCE THERAPEUTIC DELIVERY IN PRECLINICAL MODELS OF HER2-POSITIVE BREAST CANCER BRAIN METASTASIS THROUGH DEPRESSION OF BLOOD-BRAIN BARRIER EFFLUX TRANSPORT

Abstract Brain metastases from breast cancer (BCBM) are a critical complication of metastatic BC (MBC) and arise in 8-40% of all patients diagnosed with MBC, with lifetime risk varying by primary tumor subtype. Patients diagnosed with HER2-positive breast cancer (HER2+BC) are at highest risk for BCBM development, with a lifetime risk of 35-50%. While our understanding of the biology of BCBM has advanced substantially, mean survival following diagnosis of BCBM remains 7 to 15 months, making the development of innovative therapeutic approaches a critically unmet need. Advancements in drug design have improved the management of systemic MBC, however, systemic therapy for BCBM is persistently limited by the blood-brain and blood-tumor barriers (BBB, BTB). Efflux transporters are highly expressed along the membrane of BBB endothelial cells and maintain CNS homeostasis by restricting permeability of toxins and drugs. While advancements in drug design have increased the CNS penetration of select drugs in recent years, efflux transporters remain the critical limit to the delivery of anticancer agents. Importantly, the tyrosine kinase inhibitors Tucatinib and Neratinib, currently approved for HER2+BCBM, are subject to efflux by ABCB1 and ABCG2. Clinical trials of direct inhibitors of efflux transport have recurrently failed due to excess toxicity, and overcoming BBB drug efflux remains a major hurdle in the management of BCBM. While numerous signaling pathways regulating BBB efflux transport have been characterized, the utility of upstream regulators of efflux transport as therapeutic targets in BCBM remains unknown. Here, we demonstrate that the endothelin receptor (ETA/B) antagonists aprocitentan and macitentan depress BBB efflux function for up to 15 days in murine models, depress ABCB1 efflux function and protein expression in human BBB endothelial cells, and enhance the distribution of efflux substrates across the BTB in models of BCBM derived from intracardiac inoculation.