A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors

Menon, M. et al. (2019) A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors. Scientific Reports, 9, 201. (doi:10.1038/s41598-018-36447-4) (PMID:30655555) (PMCID:PMC6336890)

[img]
Preview
Text
179170.pdf - Published Version
Available under License Creative Commons Attribution.

2MB

Abstract

Inhibition of the PARP superfamily tankyrase enzymes suppresses Wnt/β-catenin signalling in tumour cells. Here, we describe here a novel, drug-like small molecule inhibitor of tankyrase MSC2504877 that inhibits the growth of APC mutant colorectal tumour cells. Parallel siRNA and drug sensitivity screens showed that the clinical CDK4/6 inhibitor palbociclib, causes enhanced sensitivity to MSC2504877. This tankyrase inhibitor-CDK4/6 inhibitor combinatorial effect is not limited to palbociclib and MSC2504877 and is elicited with other CDK4/6 inhibitors and toolbox tankyrase inhibitors. The addition of MSC2504877 to palbociclib enhances G1 cell cycle arrest and cellular senescence in tumour cells. MSC2504877 exposure suppresses the upregulation of Cyclin D2 and Cyclin E2 caused by palbociclib and enhances the suppression of phospho-Rb, providing a mechanistic explanation for these effects. The combination of MSC2504877 and palbociclib was also effective in suppressing the cellular hyperproliferative phenotype seen in Apc defective intestinal stem cells in vivo. However, the presence of an oncogenic Kras p.G12D mutation in mice reversed the effects of the MSC2504877/palbociclib combination, suggesting one molecular route that could lead to drug resistance.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Campbell, Mr Andrew and Sansom, Professor Owen and Johnson, Ms Emma
Authors: Menon, M., Elliott, R., Bowers, L., Balan, N., Rafiq, R., Costa-Cabral, S., Munkonge, F., Trinidade, I., Porter, R., Campbell, A. D., Johnson, E. R., Esdar, C., Buchstaller, H.-P., Leuthner, B., Rohdich, F., Schneider, R., Sansom, O., Wienke, D., Ashworth, A., and Lord, C. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Published Online:17 January 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Scientific Reports 9:201
Publisher Policy:Reproduced under a Creative Commons license

University Staff: Request a correction | Enlighten Editors: Update this record

Downloads per month over past year

View more statistics