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A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors
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A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors
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Journal Article
A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors
2019
Overview
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 G
1
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 45/47
/ 82/16
/ 96/98
/ Animals
/ Cell Cycle Checkpoints - drug effects
/ Cell Proliferation - drug effects
/ Cellular Senescence - drug effects
/ Colorectal Neoplasms - drug therapy
/ Colorectal Neoplasms - pathology
/ Cyclin-Dependent Kinase 4 - antagonists & inhibitors
/ Cyclin-Dependent Kinase 6 - antagonists & inhibitors
/ Enzyme Inhibitors - pharmacology
/ Enzyme Inhibitors - therapeutic use
/ Humanities and Social Sciences
/ Humans
/ Mice
/ Piperazines - therapeutic use
/ Protein Kinase Inhibitors - pharmacology
/ Protein Kinase Inhibitors - therapeutic use
/ Science
/ siRNA
/ Tankyrases - antagonists & inhibitors
/ Tumors
