dc.contributor.author | Asghar, US | |
dc.contributor.author | Barr, AR | |
dc.contributor.author | Cutts, R | |
dc.contributor.author | Beaney, M | |
dc.contributor.author | Babina, I | |
dc.contributor.author | Sampath, D | |
dc.contributor.author | Giltnane, J | |
dc.contributor.author | Lacap, JA | |
dc.contributor.author | Crocker, L | |
dc.contributor.author | Young, A | |
dc.contributor.author | Pearson, A | |
dc.contributor.author | Herrera-Abreu, MT | |
dc.contributor.author | Bakal, C | |
dc.contributor.author | Turner, NC | |
dc.date.accessioned | 2017-09-06T10:43:57Z | |
dc.date.issued | 2017-09-15 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (18), pp. 5561 - 5572 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/811 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-17-0369 | |
dc.description.abstract | Purpose: 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.format | Print-Electronic | |
dc.format.extent | 5561 - 5572 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Disease Models, Animal | |
dc.subject | Piperazines | |
dc.subject | Pyridines | |
dc.subject | Receptors, Androgen | |
dc.subject | Antineoplastic Agents | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Signal Transduction | |
dc.subject | Mitosis | |
dc.subject | Cell Proliferation | |
dc.subject | Cell Survival | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Phenotype | |
dc.subject | Female | |
dc.subject | Cyclin-Dependent Kinase 4 | |
dc.subject | Cyclin-Dependent Kinase 6 | |
dc.subject | Molecular Imaging | |
dc.subject | Phosphatidylinositol 3-Kinases | |
dc.subject | Time-Lapse Imaging | |
dc.subject | Single-Cell Analysis | |
dc.subject | Triple Negative Breast Neoplasms | |
dc.title | Single-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-06-05 | |
rioxxterms.funder | The Institute of Cancer Research | |
rioxxterms.identifier.project | Unspecified | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-17-0369 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2017-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.issue | 18 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 23 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Molecular Oncology | |
icr.researchteam | Dynamical Cell Systems | |
dc.contributor.icrauthor | Asghar, Uzma | |
dc.contributor.icrauthor | Barr, Alexis | |
dc.contributor.icrauthor | Cutts, Rosalind | |
dc.contributor.icrauthor | Pearson, Alex | |
dc.contributor.icrauthor | Bakal, Christopher | |
dc.contributor.icrauthor | Turner, Nicholas | |