Abstract PO-040: Nischarin is expressed in pancreatic ductal adenocarcinoma and is a potential target for drug repurposing

The objective of this study was to examine the expression of Nischarin (NISCH) in pancreatic ductal adenocarcinoma (PDAC), and its potential as a target for drug repurposing. NISCH has been described as a tumor suppressor in breast and ovarian cancers, and there are several clinically approved agonists for this receptor. NISCH has also been reported as a scaffolding protein with a role in cell adhesion, invasion and metabolism – aspects of the PDAC biology that are of interest for therapeutical intervention. We examined mRNA and protein expression of NISCH in publicly available datasets, patient tumor samples, representative PDAC cell lines and patient-derived stellate cells. We found that NISCH is a prognostic marker in PDAC patients and that it is expressed in both cancer cells and cancer-associated stroma. Gene set enrichment analysis showed that NISCH expression was associated with the regulation of cell motility, cell cycle and energy metabolism. Indeed, NISCH knockdown in cancer cells induced reorganization of the actin cytoskeleton. Next, we tested the effects of three clinically approved NISCH agonists (rilmenidine, clonidine and moxonidine) on cancer cells and cancer-associated fibroblasts (CAFs). We found that rilmenidine, agonist with the highest affinity for the NISCH receptor, had the most potent effect. Rilmenidine impaired cancer cell adhesion, limited migration and decreased production of pro-metastatic cytokines and extracellular matrix deposition in cancer cell-CAF co-cultures. Our study lays a ground for more extensive examination of the role of NISCH in PDAC and implies that NISCH agonists may be good candidates for drug repurposing in this type of cancer. Citation Format: Jelena Grahovac, Marijana Pavlovic, Marija Ostojic, Kristina Zivic, Daniel Galun, Tatjana Srdic-Rajic. Nischarin is expressed in pancreatic ductal adenocarcinoma and is a potential target for drug repurposing [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-040.