Monensin and its derivatives increase MHC Class I and II presentations in breast cancer

Abstract ID 97781 Poster Board 285 The recent approval of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of metastatic breast cancer (BC). However, approximately 30% of patients remain unresponsive. The effectiveness of ICIs depends on the effective presentation of tumor-specific antigens by cancer cells. Consequently, augmenting this presentation holds the potential to enhance the efficacy of ICI treatment. Monensin (MON), a naturally occurring ionophore antibiotic with anti-cancer properties, emerges as a promising candidate for drug repositioning. In the present study, we assessed the activity of ester and urethane derivatives of MON in cell monolayer and organoid models of both human and mouse BC. We identified several compounds with increased potency and selectivity against MDA-MB-231, MDA-MB-468, E0771, and 4T1 cell lines compared to the parent MON. Further studies showed that both MON and its most potent derivatives increased Major Histocompatibility Complex (MHC) class I and II presentation. Additionally, these compounds significantly downregulated Programmed death-ligand 1 (PD-L1) expression in BC cell lines. The present findings suggest that MON is a potential model for new therapeutics, which can serve as single agents or be used in combination with existing ICIs for the treatment of metastatic BC. This project was supported by the Translational Research Institute, grant KL2 TR003108 through the NIH National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.