WNT signalling is a complex cascade and there is extensive crosstalk with other pathways.
WNT signalling has crucial roles in both normal homeostasis and disease, and thereby there has been considerable difficulty in safely targeting the WNT pathway, thus hampering development to date.
There are multiple points of intervention in the WNT signalling cascade that have been investigated; however, many of them may be limited from the standpoint of therapeutic efficacy owing to on-target side effects.
WNT signalling has crucial roles in stem cells — both normal and cancer stem cells — in both the maintenance of potency and initiation of differentiation.
Currently, several specific inhibitors and modulators of WNT signalling have entered clinical trials. Preliminary results and future prospects are discussed.
WNT–β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.
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Support from the USC Norris Comprehensive Cancer Center (Support Grant P30 CA014089) and the US National Institutes of Health (NIH) grants 1R01CA166161-01A1, 1R21NS074392-01, 1R21AI105057-01 and NIH 1R01 HL112638-01 are gratefully acknowledged. I thank J.-L. Teo for critical review and assistance with preparation of this manuscript. As with any attempt to review a broad and dynamically changing field, this is a snapshot of the current status. I apologize for any unintended omissions and oversights.
The author is a consultant and equity holder in Prism Pharma Co. Ltd.
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Kahn, M. Can we safely target the WNT pathway?. Nat Rev Drug Discov 13, 513–532 (2014). https://doi.org/10.1038/nrd4233
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