A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors.
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Date
2019-01-17ICR Author
Author
Menon, M
Elliott, R
Bowers, L
Balan, N
Rafiq, R
Costa-Cabral, S
Munkonge, F
Trinidade, I
Porter, R
Campbell, AD
Johnson, ER
Esdar, C
Buchstaller, H-P
Leuthner, B
Rohdich, F
Schneider, R
Sansom, O
Wienke, D
Ashworth, A
Lord, CJ
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
Cell Line, Tumor
Animals
Humans
Mice
Colorectal Neoplasms
Piperazines
Pyridines
Tankyrases
Enzyme Inhibitors
Protein Kinase Inhibitors
Cell Proliferation
Drug Synergism
Drug Resistance, Neoplasm
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Cell Cycle Checkpoints
Cellular Senescence
Research team
Gene Function
Language
eng
Date accepted
2018-11-07
License start date
2019-01-17
Citation
Scientific reports, 2019, 9 (1), pp. 201 - ?
Publisher
NATURE PUBLISHING GROUP