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dc.contributor.authorAarts, M
dc.contributor.authorSharpe, R
dc.contributor.authorGarcia-Murillas, I
dc.contributor.authorGevensleben, H
dc.contributor.authorHurd, MS
dc.contributor.authorShumway, SD
dc.contributor.authorToniatti, C
dc.contributor.authorAshworth, A
dc.contributor.authorTurner, NC
dc.date.accessioned2018-07-31T14:16:17Z
dc.date.issued2012-06
dc.identifier.citationCancer discovery, 2012, 2 (6), pp. 524 - 539
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2235
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.cd-11-0320
dc.description.abstractInhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. We show that WEE1 inhibition forces S-phase-arrested cells directly into mitosis without completing DNA synthesis, resulting in highly abnormal mitoses characterized by dispersed chromosomes and disorganized bipolar spindles, ultimately resulting in mitotic exit with gross micronuclei formation and apoptosis. This mechanism of cell death is shared by CHK1 inhibitors, and combined WEE1 and CHK1 inhibition forces mitotic entry from S-phase in the absence of chemotherapy. We show that p53/p21 inactivation combined with high expression of mitotic cyclins and EZH2 predispose to mitotic entry during S-phase with cells reliant on WEE1 to prevent premature cyclin-dependent kinase (CDK)1 activation. These features are characteristic of aggressive breast, and other, cancers for which WEE1 inhibitor combinations represent a promising targeted therapy.
dc.formatPrint-Electronic
dc.format.extent524 - 539
dc.languageeng
dc.language.isoeng
dc.subjectCell Line
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMice, SCID
dc.subjectBreast Neoplasms
dc.subjectUrea
dc.subjectPyrazoles
dc.subjectPyrimidines
dc.subjectPyrimidinones
dc.subjectThiazoles
dc.subjectThiophenes
dc.subjectQuinolines
dc.subjectProtein Kinases
dc.subjectCyclins
dc.subjectCell Cycle Proteins
dc.subjectDNA-Binding Proteins
dc.subjectNuclear Proteins
dc.subjectTranscription Factors
dc.subjectDeoxycytidine
dc.subjectAntineoplastic Agents
dc.subjectProtein Kinase Inhibitors
dc.subjectTumor Burden
dc.subjectXenograft Model Antitumor Assays
dc.subjectMitosis
dc.subjectS Phase
dc.subjectApoptosis
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectFemale
dc.subjectTumor Suppressor Protein p53
dc.subjectProtein-Tyrosine Kinases
dc.subjectPolycomb Repressive Complex 2
dc.subjectCheckpoint Kinase 1
dc.subjectEnhancer of Zeste Homolog 2 Protein
dc.titleForced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1.
dc.typeJournal Article
rioxxterms.versionofrecord10.1158/2159-8290.cd-11-0320
rioxxterms.licenseref.startdate2012-06
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer discovery
pubs.issue6
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/Breast Cancer Research/Molecular Oncology
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/Breast Cancer Research/Molecular Oncology
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.volume2en_US
pubs.embargo.termsNot known
icr.researchteamMolecular Oncologyen_US
icr.researchteamGene Functionen_US
dc.contributor.icrauthorAarts, Mariekeen
dc.contributor.icrauthorAshworth, Alanen
dc.contributor.icrauthorTurner, Nicholasen
dc.contributor.icrauthorGarcia-Murillas, Isaacen


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