dc.contributor.author | Witkiewicz, AK | |
dc.contributor.author | Chung, S | |
dc.contributor.author | Brough, R | |
dc.contributor.author | Vail, P | |
dc.contributor.author | Franco, J | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Knudsen, ES | |
dc.date.accessioned | 2020-09-21T15:57:21Z | |
dc.date.issued | 2018-01-30 | |
dc.identifier.citation | Cell reports, 2018, 22 (5), pp. 1185 - 1199 | |
dc.identifier.issn | 2211-1247 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4078 | |
dc.identifier.eissn | 2211-1247 | |
dc.identifier.doi | 10.1016/j.celrep.2018.01.022 | |
dc.description.abstract | Approximately 30% of triple-negative breast cancers (TNBCs) exhibit functional loss of the RB tumor suppressor, suggesting a target for precision intervention. Here, we use drug screens to identify agents specifically antagonized by the retinoblastoma tumor suppressor (RB) using CDK4/6 inhibitors. A number of candidate RB-synthetic lethal small molecules were identified, including anti-helmenthics, chemotherapeutic agents, and small-molecule inhibitors targeting DNA-damage checkpoints (e.g., CHK) and chromosome segregation (e.g., PLK1). Counter-screens using isogenic TNBC tumor cell lines and cell panels with varying endogenous RB statuses confirmed that therapeutic effects were robust and selective for RB loss of function. By analyzing TNBC clinical specimens, RB-deficient tumors were found to express high levels of CHK1 and PLK1. Loss of RB specifically resulted in loss of checkpoint functions governing DNA replication, yielding increased drug sensitivity. Xenograft models demonstrated RB-selective efficacy of CHK inhibitors. This study supports the possibility of selectively targeting RB loss in the treatment of TNBC. | |
dc.format | Print | |
dc.format.extent | 1185 - 1199 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | CELL PRESS | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Protein-Serine-Threonine Kinases | |
dc.subject | Cell Cycle Proteins | |
dc.subject | Retinoblastoma Protein | |
dc.subject | Proto-Oncogene Proteins | |
dc.subject | Antineoplastic Agents | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Drug Screening Assays, Antitumor | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Cell Proliferation | |
dc.subject | Female | |
dc.subject | Cell Cycle Checkpoints | |
dc.subject | Triple Negative Breast Neoplasms | |
dc.subject | Checkpoint Kinase 1 | |
dc.title | Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-01-08 | |
rioxxterms.versionofrecord | 10.1016/j.celrep.2018.01.022 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2018-01 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cell reports | |
pubs.issue | 5 | |
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/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-status | Published | |
pubs.volume | 22 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Lord, Christopher | |