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dc.contributor.authorAsghar, US
dc.contributor.authorBarr, AR
dc.contributor.authorCutts, R
dc.contributor.authorBeaney, M
dc.contributor.authorBabina, I
dc.contributor.authorSampath, D
dc.contributor.authorGiltnane, J
dc.contributor.authorLacap, JA
dc.contributor.authorCrocker, L
dc.contributor.authorYoung, A
dc.contributor.authorPearson, A
dc.contributor.authorHerrera-Abreu, MT
dc.contributor.authorBakal, C
dc.contributor.authorTurner, NC
dc.date.accessioned2017-09-06T10:43:57Z
dc.date.issued2017-09
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (18), pp. 5561 - 5572
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/811
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-17-0369
dc.description.abstractPurpose: Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer that is associated with a poor prognosis. We evaluated the activity of CDK4/6 inhibitors across the TNBC subtypes and investigated mechanisms of sensitivity. Experimental Design: A panel of cell lines representative of TNBC was tested for in vitro and in vivo sensitivity to CDK4/6 inhibition. A fluorescent CDK2 activity reporter was used for single-cell analysis in conjunction with time-lapse imaging. Results: The luminal androgen receptor (LAR) subtype of TNBC was highly sensitive to CDK4/6 inhibition both in vitro ( P < 0.001 LAR vs. basal-like) and in vivo in MDA-MB-453 LAR cell line xenografts. Single-cell analysis of CDK2 activity demonstrated differences in cell-cycle dynamics between LAR and basal-like cells. Palbociclib-sensitive LAR cells exit mitosis with low levels of CDK2 activity, into a quiescent state that requires CDK4/6 activity for cell-cycle reentry. Palbociclib-resistant basal-like cells exit mitosis directly into a proliferative state, with high levels of CDK2 activity, bypassing the restriction point and the requirement for CDK4/6 activity. High CDK2 activity after mitosis is driven by temporal deregulation of cyclin E1 expression. CDK4/6 inhibitors were synergistic with PI3 kinase inhibitors in PIK3CA -mutant TNBC cell lines, extending CDK4/6 inhibitor sensitivity to additional TNBC subtypes. Conclusions: Cell-cycle dynamics determine the response to CDK4/6 inhibition in TNBC. CDK4/6 inhibitors, alone and in combination, are a novel therapeutic strategy for specific subgroups of TNBC. Clin Cancer Res; 23(18); 5561-72. ©2017 AACR .
dc.formatPrint-Electronic
dc.format.extent5561 - 5572
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectDisease Models, Animal
dc.subjectPiperazines
dc.subjectPyridines
dc.subjectReceptors, Androgen
dc.subjectAntineoplastic Agents
dc.subjectProtein Kinase Inhibitors
dc.subjectSignal Transduction
dc.subjectMitosis
dc.subjectCell Proliferation
dc.subjectCell Survival
dc.subjectDrug Resistance, Neoplasm
dc.subjectPhenotype
dc.subjectFemale
dc.subjectCyclin-Dependent Kinase 4
dc.subjectCyclin-Dependent Kinase 6
dc.subjectMolecular Imaging
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectTime-Lapse Imaging
dc.subjectSingle-Cell Analysis
dc.subjectTriple Negative Breast Neoplasms
dc.titleSingle-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer.
dc.typeJournal Article
dcterms.dateAccepted2017-06-05
rioxxterms.funderThe Institute of Cancer Research
rioxxterms.identifier.projectUnspecified
rioxxterms.versionofrecord10.1158/1078-0432.ccr-17-0369
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue18
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/Molecular Oncology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Dynamical Cell Systems
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/Molecular Oncology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Dynamical Cell Systems
pubs.publication-statusPublished
pubs.volume23
pubs.embargo.termsNot known
icr.researchteamMolecular Oncologyen_US
icr.researchteamDynamical Cell Systemsen_US
dc.contributor.icrauthorBakal, Christopheren
dc.contributor.icrauthorBarr, Alexisen
dc.contributor.icrauthorAsghar, Uzmaen
dc.contributor.icrauthorTurner, Nicholasen


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