AUTHOR=Di Giorgio Cristina , Bellini Rachele , Lupia Antonio , Massa Carmen , Bordoni Martina , Marchianò Silvia , Rosselli Rosalinda , Sepe Valentina , Rapacciuolo Pasquale , Moraca Federica , Morretta Elva , Ricci Patrizia , Urbani Ginevra , Monti Maria Chiara , Biagioli Michele , Distrutti Eleonora , Catalanotti Bruno , Zampella Angela , Fiorucci Stefano 

TITLE=Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1140730

DOI=10.3389/fonc.2023.1140730

ISSN=2234-943X

ABSTRACT=<sec><title>Introduction</title><p>The leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).</p></sec><sec><title>Methods</title><p>Herein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues. </p></sec><sec><title>Results</title><p>The transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By <italic>in vitro</italic> assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC<sub>50</sub> of 3.8 µM.</p></sec><sec><title>Discussion</title><p>BAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.</p></sec>