OC-14 Involvement of the ERG1 potassium channel in cholangiocarcinoma cell biology

Background and Aim: Due to the lack of proper biomarkers and potentially effective treatments, the management of cholangiocar- cinoma (CCA) is still challenging. In this view, ion channels have been proven to be novel biomarkers as well as new targets for cancer therapy, due to their easy druggability. The voltage-gated K + channel hERG1 exert pleiotropic effects in cancer cells. Thus, this study explored the influence of hERG1 in intrahepatic CCA (iCCA) susceptibility. Methods: Validation of h ERG1 in iCCA tissues was performed in TCGA database. In vitro experiments were assessed to estimate the impact of h ERG1 inhibition on cell function in iCCA cell lines (HUCCT1, CCLP1, CCA4). Results: Significant difference in h ERG1 gene expression was observed between iCCA and normal tissue samples. Similarly, iCCA cell lines significantly showed high protein content of hERG1 compared to normal cholangiocytes (NHC3). Treatment with E4031, a selective hERG1 inhibitor as well ge- netic depletion (siRNA), showed, albeit limited impact of cell growth, a substantial reduction of invasive capability of iCCA cells. Moreover, immunoprecipitation assay and immunofluorescence re- vealed the formation of an active macromolecular complex with β1 integrin responsible for VEGF-A activation through the phosphorylation of AKT signaling. Furthermore, treatment with the bispecific antibody (scDb: single-chain Diabody) that binds the hERG1- β1 complex, nega- tively impacted invasiveness of iCCA cells as well as expression of epithelial to mesenchymal genes. Importantly in vitro co-treatment with scDb and cisplatin-gemcitabine, significantly reduced growth of iCCA cells. Conclusions: This study suggests that hERG1 may play a critical role in the initiation and progression of intrahepatic CCA, highlighting its potential as a therapeutic target.