Therapeutic window for Wnt-driven cancers: Role of Porcupine inhibitor

Abstract

Wnt signaling plays a critical role in carcinogenesis; many studies over the last two decades have identified numerous signaling components that have helped to build a molecular framework for the many branches of the Wnt signal transduction pathway. However, the diverse function, integration and specificity of the Wnt signaling are still unclear. The success of Wnt pathway inhibitors has been limited for long-time by the narrow therapeutic window afforded by the requirement for Wnt signaling in normal tissue homeostasis and the lack of predictive biomarkers of response. Porcupine is a membrane bound O-acyltransferase enzyme that is required for and dedicated to palmitoylating Wnt ligands, a necessary step in the process of Wnt ligand secretion. Inhibition of Porcupine blocks Wnt dependent activities, including LRP6 phosphorylation and the expression of Wnt target genes, such as Axin2, which in turn reduces the growth of cancer cells dependent on autocrine or paracrine Wnt signaling. LGK974 is a highly potent, selective and orally bioavailable Porcupine inhibitor and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV–Wnt1, a human head and neck squamous cell carcinoma model (HN30) and RNF43-mutant pancreatic xenograft models. In this review, we will summarize the most recent advances in our understanding of these Wnt signaling pathways and the role of Porcupine in inhibition of Wnt activity.