Abstract B13: ETC-159 is a novel PORCN inhibitor effective for treatment of Wnt-addicted genetically defined cancers

Pathologic expression of Wnts is found in cancers, fibrosis and other diseases, hence there is considerable interest in blocking Wnt signaling to achieve therapeutic benefit. Post-translational palmitoleation of Wnts at a highly conserved serine residue is essential for their secretion and function. We have pursued a strategy to block all Wnt-dependent pathways concomitantly using a small molecule inhibitor of the enzyme PORCN that is required for Wnt O-palmitoleation. As Wnt pathway inhibitors advance to clinical trials, the paucity of well-defined biomarkers makes it challenging to monitor response to therapeutics.We have developed a novel PORCN inhibitor ETC-159, which has remarkable efficacy in pre-clinical models of RNF43-mutant pancreatic and ovarian cancers and RSPO3-translocation bearing colorectal cancer patient derived xenografts. ETC-159 reverses Wnt dependent pathology by promoting cellular differentiation. Consistent with the role of Wnt/β-catenin signaling in regulation of diverse cellular functions, RNA sequencing of these ETC-159 sensitive, Wnt driven cancers has revealed significant remodeling of the transcriptome on treatment with ETC-159 with a decrease of cell cycle, stem cell, and proliferation genes and an increase in differentiation markers. Our studies show that coordinate regulation of NOTUM and AXIN2 gene expression may be a useful predictor of sensitivity to PORCN inhibitors. NOTUM is a secreted protein and its levels in serum correlate with tu...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Signaling Pathways: Wnt: Poster Presentations - Proffered Abstracts Source Type: research