Pharmacological interventions in the Wnt pathway: inhibition of Wnt secretion versus disrupting the protein–protein interfaces of nuclear factors

Abstract

Mutations in components of the Wnt pathways are a frequent cause of many human diseases, particularly cancer. Despite the fact that a causative link between aberrant Wnt signalling and many types of human cancers was established more than a decade ago, no Wnt signalling inhibitors have made it into the clinic so far. One reason for this is that no pathway‐specific kinase is known. Additionally, targeting the protein–protein interactions needed to transduce the signal has not met with success so far. Complicating the search for and use of inhibitors is the complexity of the cascades triggered by the Wnts and their paramount biological importance. Wnt/β‐catenin signalling is involved in virtually all aspects of embryonic development and in the control of the homeostasis of adult tissues. Encouragingly, however, in recent years, first successes with Wnt‐pathway inhibitors have been reported in mouse models of disease. In this review, we summarize possible roads to follow during the quest to pharmacologically modulate the Wnt signalling pathway in cancer. Linked Articles This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc

TBX3 acts as tissue-specific component of the Wnt/β-catenin enhanceosome

“…Importantly, BCL9/9L and PYGO proteins were found to significantly contribute to the malignant traits typical of Wnt-induced CRCs (Deka et al, 2010;Gay et al, 2019;Jiang et al, 2020;Mani et al, 2009;Mieszczanek et al, 2019;Moor et al, 2015;Talla and Brembeck, 2016). These observations provided impetus to consider the BCL9/PYGO axis as relevant "targetable" unit in CRC (Lyou et al, 2017;Mieszczanek et al, 2019;Talla and Brembeck, 2016;Zimmerli et al, 2017).…”

Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy

“…A great deal of work has been performed to uncover the intricacies of the signal transduction steps at the cell surface and the cytoplasm to better understand the normal and dysfunctional activity of Wnt signalling. Recent reviews published elsewhere and in this issue describe our current understanding of these steps in detail (Niehrs and Acebron, ; DeBruine et al, ; Driehuis and Clevers, ; Nusse and Clevers, ; van Kappel and Maurice, ; Zimmerli et al, ).…”

Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma

“…Although activating mutations in intracellular components of the pathway induce Wnt ligand-independent signaling in cancer cells, the importance of ligand-dependent signaling is increasingly appreciated 2 . Targeted therapies against Wnt ligands show good preclinical responses and are tested in human trials 3 . A major drawback of the available treatments is that they non-specifically target groups of ligands and receptors and are associated with a high frequency of adverse events 3 .…”