Monensin as potential drug for treatment of SLeX-positive tumors

Abstract

AbstractColorectal (CRC) and gastric (GC) cancers remain the top lethal cancers and targeted therapies in this setting are still very limited. Sialyl Lewis X (SLeX), a cancer-associated glycan highly expressed in both CRC and GC, plays a crucial role in cancer cell dissemination and metastasis. Thus, presenting a promising but still underexplored therapeutic target. In this work, we performed a high-throughput screening (HTS) approach to identify potential inhibitors of SLeX expression on cancer cells. Two libraries including a total of 7836 compounds were screened and monensin emerged as a promising SLeX inhibitor. Monensin promoted structural alterations in the secretory pathway, particularly at the Golgi apparatus, impacting proteinO-glycosylation and secretion. RNAseq transcriptomic analysis uncovered significant alterations in Gene Ontology (GO) terms associated with protein misfolding, target to the membrane, as well as, epithelial cell-cell adhesion protein.In vitrostudies showed that, upon treatment with monensin, SLeX-positive cancer cells showed reduced viability, concomitant with decreased motility and invasive capacities. Usingin vivoxenograft models of chick embryo chorioallantoic membrane (CAM) and nude mice, revealed that monensin reduced tumor formation and invasion. Pre-clinical validation using gastric cancer patient-derived organoids (PDOs) and organoid xenotransplants in mice further underscored the clinical potential of monensin in suppressing the growth of SLeX- positive tumors. Overall, our findings set the ground for further evaluation of monensin as a novel therapeutic agent in GC and CRC in the clinical setting.