Targeting ligand-dependent wnt pathway dysregulation in gastrointestinal cancers through porcupine inhibition

Flanagan, D. J., Woodcock, S. A., Phillips, C., Eagle, C. and Sansom, O. J. (2022) Targeting ligand-dependent wnt pathway dysregulation in gastrointestinal cancers through porcupine inhibition. Pharmacology and Therapeutics, 238, 108179. (doi: 10.1016/j.pharmthera.2022.108179) (PMID:35358569)

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Abstract

Gastrointestinal cancers are responsible for more cancer deaths than any other system of the body. This review summarises how Wnt pathway dysregulation contributes to the development of the most common gastrointestinal cancers, with a particular focus on the nature and frequency of upstream pathway aberrations. Tumors with upstream aberrations maintain a dependency on the presence of functional Wnt ligand, and are predicted to be tractable to inhibitors of Porcupine, an enzyme that plays a key role in Wnt secretion. We summarise available pre-clinical efficacy data from Porcupine inhibitors in vitro and in vivo, as well as potential toxicities and the data from early phase clinical trials. We appraise the rationale for biomarker-defined targeted approaches, as well as outlining future opportunities for combination with other therapeutics.

Item Type:Articles
Additional Information:O.J. S acknowledges core grant A17196 and A31287 from Cancer Research UK
Keywords:Porcupine inhibitor, RSPO, clinical trials, RNF43, gastrointestinal cancer, Wnt
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Flanagan, Dr Dustin and Sansom, Professor Owen
Authors: Flanagan, D. J., Woodcock, S. A., Phillips, C., Eagle, C., and Sansom, O. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Pharmacology and Therapeutics
Publisher:Elsevier
ISSN:0163-7258
ISSN (Online):1879-016X
Published Online:28 March 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Pharmacology and Therapeutics 238: 108179
Publisher Policy:Reproduced under a Creative Commons License

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