dc.contributor.author | Costa-Cabral, S | |
dc.contributor.author | Brough, R | |
dc.contributor.author | Konde, A | |
dc.contributor.author | Aarts, M | |
dc.contributor.author | Campbell, J | |
dc.contributor.author | Marinari, E | |
dc.contributor.author | Riffell, J | |
dc.contributor.author | Bardelli, A | |
dc.contributor.author | Torrance, C | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Ashworth, A | |
dc.date.accessioned | 2016-09-14T09:51:28Z | |
dc.date.issued | 2016-02-16 | |
dc.identifier.citation | PloS one, 2016, 11 (2), pp. e0149099 - ? | |
dc.identifier.issn | 1932-6203 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/110 | |
dc.identifier.eissn | 1932-6203 | |
dc.identifier.doi | 10.1371/journal.pone.0149099 | |
dc.description.abstract | Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent kinase, CDK1. This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models. This established that the KRAS/CDK1 synthetic lethality applies in tumour cells with either amino acid position 12 (p.G12V, pG12D, p.G12S) or amino acid position 13 (p.G13D) KRAS mutations and can also be replicated in vivo in a xenograft model using a small molecule CDK1 inhibitor. Mechanistically, CDK1 inhibition caused a reduction in the S-phase fraction of KRAS mutant cells, an effect also characterised by modulation of Rb, a master control of the G1/S checkpoint. Taken together, these observations suggest that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation. | |
dc.format | Electronic-eCollection | |
dc.format.extent | e0149099 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | PUBLIC LIBRARY SCIENCE | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, Nude | |
dc.subject | Colorectal Neoplasms | |
dc.subject | Pancreatic Neoplasms | |
dc.subject | Imidazoles | |
dc.subject | Pyrimidines | |
dc.subject | Thiazoles | |
dc.subject | Quinolines | |
dc.subject | Cyclin-Dependent Kinases | |
dc.subject | CDC2 Protein Kinase | |
dc.subject | RNA, Small Interfering | |
dc.subject | Antineoplastic Agents | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Survival Analysis | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Signal Transduction | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Mutation | |
dc.subject | Genes, Lethal | |
dc.subject | Female | |
dc.subject | Proto-Oncogene Proteins p21(ras) | |
dc.subject | High-Throughput Screening Assays | |
dc.subject | G1 Phase Cell Cycle Checkpoints | |
dc.title | CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-01-27 | |
rioxxterms.versionofrecord | 10.1371/journal.pone.0149099 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-01 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | PloS one | |
pubs.issue | 2 | |
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 | 11 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Campbell, James | |
dc.contributor.icrauthor | Lord, Christopher | |