PACM-13 ENDOTHELIN RECEPTOR ANTAGONISTS ENHANCE NERATINIB EFFICACY IN PRECLINICAL MODELS OF BREAST CANCER BRAIN METASTASIS THROUGH DEPRESSION OF BLOOD-BRAIN BARRIER EFFLUX TRANSPORT

Abstract

Brain metastases from breast cancer (BCBM) are a significant cause of BC mortality, and patients with HER2-positive disease (HER2+BC) are at highest risk for BCBM (35-50%). Despite advances in therapy for HER2+BC, median survival for patients with central nervous system (CNS) recurrence has stagnated at 18 months. The risk of BCBM for patients with HER2+BC and the limitations of current systemic therapies highlight a critical need for novel approaches to overcome CNS-specific mechanisms of drug resistance. The blood-brain barrier (BBB) is a cellular network comprising brain capillary endothelium, pericytes, astrocytes, and neuronal inputs, which forms the blood-tumor barrier (BTB) during CNS tumor invasion. ATP-binding cassette (ABC) efflux transporters are highly expressed at the luminal membrane of BBB/BTB endothelial cells, and limit efficacy of systemic therapies by restricting drug accumulation within CNS tumors. Numerous inhibitors of ABC transporters have been developed, however, none have generated a clinical benefit due to excess toxicity. Endothelin receptors (ETA/B), G-coupled protein receptors expressed throughout the cardiovascular system, interact with multiple pathways regulating BBB efflux transporters. While regulation of BBB efflux transport has been extensively studied, pharmacologic targeting of upstream regulators to overcome BBB efflux and enhance CNS drug delivery remains an understudied area. Here, we demonstrate that ETA and ETB are overexpressed in BTB endothelium in human and murine samples, and utilize pharmacokinetic assays to demonstrate that ETA/B antagonists depress ABCB1-mediated BBB efflux in vitro and in vivo, thereby enhancing CNS delivery of the HER2 inhibitor neratinib. Further, addition of ETA/B antagonists to neratinib therapy significantly extends survival and slows brain metastatic progression in preclinical models of brain metastasis from HER2+BC, suggesting their viability as a systemic blood-brain barrier-directed therapy for BCBM.