Abstract 2939: ETC159, a porcupine inhibitor, exhibits synergism with PI3K inhibitors in 3-dimensional cell culture

Abstract

Abstract Aberrations in WNT signaling, a pathway regulated by a family of secreted glycoproteins known as WNTs, is implicated as a cause for cancer. Post-translational modification of WNTs by porcupine is critical for their activity and eventual activation of the WNT pathway. ETC-159 is an orally available, potent porcupine inhibitor. Addition of ETC-159 suppresses cancer proliferation in several cell lines by blocking the secretion and activity of all WNTs. Nevertheless, tumor growth is driven by complex molecular interactions that dysregulate several pathways at any one time. Thus, early drug discovery studies have increasingly evolved to target multiple molecules or pathways. As therapeutic approaches using combinations of drugs directed at multiple targets can improve treatment response, in this study we explored the possibility of identifying compounds that are synergistic with ETC-159. Unlike conventional two-dimensional combination drug screening, we used the three-dimensional soft agar colony formation assays for the study. Dose-response curves were first independently established to obtain the EC50 ranges for each drug, before proceeding to combination treatments. Using the Chou-Talalay Drug Combination Software, CompuSyn, we identified several inhibitors, which target the PI3K pathway, to act synergistically with ETC-159 in pancreatic cell lines HPAF-II, ASPC-1 and CFPAC-I. Similar treatments in nonpancreatic cell lines indicated that the observed synergism was not cell-line specific, hence highlighting the applicability of such combination treatments for different cancers. Citation Format: Sugunavathi Sepramaniam, Xin Hui Chew, Kao Chin Ngeow, May Ann Lee. ETC159, a porcupine inhibitor, exhibits synergism with PI3K inhibitors in 3-dimensional cell culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2939.