Can we safely target the WNT pathway?

The WNT pathway has a vast array of functions and aberrant WNT signalling is correspondingly implicated in numerous diseases, including cancer, fibrosis and nervous system disorders. Kahn discusses our understanding of this developmentally important pathway, the complexities associated with safely targeting it therapeutically and WNT-modulating agents that are currently being investigated. 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.