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Sci Rep. 2019 Jan 17;9(1):201. doi: 10.1038/s41598-018-36447-4.

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

Author information

1
CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
2
The Wellcome Trust, Euston Road, London, NW1 2BE, UK.
3
CRUK Beatson Institute, Switchback Rd, Bearsden, Glasgow, G61 1BD, UK.
4
Merck KGaA, Biopharma Research & Development, Frankfurter Str. 250, 64293, Darmstadt, Germany.
5
Merck KGaA, Biopharma Research & Development, Frankfurter Str. 250, 64293, Darmstadt, Germany. Dirk.Wienke@merckgroup.com.
6
CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK. Alan.Ashworth@ucsf.edu.
7
UCSF Helen Diller Family Comprehensive Cancer Centre, San Francisco, 94158, USA. Alan.Ashworth@ucsf.edu.
8
CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK. Chris.Lord@icr.ac.uk.

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.

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