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)

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