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dc.contributor.authorMenon, M
dc.contributor.authorElliott, R
dc.contributor.authorBowers, L
dc.contributor.authorBalan, N
dc.contributor.authorRafiq, R
dc.contributor.authorCosta-Cabral, S
dc.contributor.authorMunkonge, F
dc.contributor.authorTrinidade, I
dc.contributor.authorPorter, R
dc.contributor.authorCampbell, AD
dc.contributor.authorJohnson, ER
dc.contributor.authorEsdar, C
dc.contributor.authorBuchstaller, H-P
dc.contributor.authorLeuthner, B
dc.contributor.authorRohdich, F
dc.contributor.authorSchneider, R
dc.contributor.authorSansom, O
dc.contributor.authorWienke, D
dc.contributor.authorAshworth, A
dc.contributor.authorLord, CJ
dc.date.accessioned2018-12-17T11:27:53Z
dc.date.issued2019-01-17
dc.identifier.citationScientific reports, 2019, 9 (1), pp. 201 - ?
dc.identifier.issn2045-2322
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2974
dc.identifier.eissn2045-2322
dc.identifier.doi10.1038/s41598-018-36447-4
dc.description.abstractInhibition 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.
dc.formatElectronic
dc.format.extent201 - ?
dc.languageeng
dc.language.isoeng
dc.publisherNATURE PUBLISHING GROUP
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectColorectal Neoplasms
dc.subjectPiperazines
dc.subjectPyridines
dc.subjectTankyrases
dc.subjectEnzyme Inhibitors
dc.subjectProtein Kinase Inhibitors
dc.subjectCell Proliferation
dc.subjectDrug Synergism
dc.subjectDrug Resistance, Neoplasm
dc.subjectCyclin-Dependent Kinase 4
dc.subjectCyclin-Dependent Kinase 6
dc.subjectCell Cycle Checkpoints
dc.subjectCellular Senescence
dc.titleA novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors.
dc.typeJournal Article
dcterms.dateAccepted2018-11-07
rioxxterms.versionofrecord10.1038/s41598-018-36447-4
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-01-17
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfScientific reports
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume9
pubs.embargo.termsNot known
icr.researchteamGene Function
dc.contributor.icrauthorLord, Christopher


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