Show simple item record

dc.contributor.authorCosta-Cabral, S
dc.contributor.authorBrough, R
dc.contributor.authorKonde, A
dc.contributor.authorAarts, M
dc.contributor.authorCampbell, J
dc.contributor.authorMarinari, E
dc.contributor.authorRiffell, J
dc.contributor.authorBardelli, A
dc.contributor.authorTorrance, C
dc.contributor.authorLord, CJ
dc.contributor.authorAshworth, A
dc.date.accessioned2016-09-14T09:51:28Z
dc.date.issued2016-01
dc.identifier.citationPloS one, 2016, 11 (2), pp. e0149099 - ?
dc.identifier.issn1932-6203
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/110
dc.identifier.eissn1932-6203
dc.identifier.doi10.1371/journal.pone.0149099
dc.description.abstractActivating 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.formatElectronic-eCollection
dc.format.extente0149099 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectMice, Inbred BALB C
dc.subjectHumans
dc.subjectMice
dc.subjectMice, Nude
dc.subjectColorectal Neoplasms
dc.subjectPancreatic Neoplasms
dc.subjectImidazoles
dc.subjectPyrimidines
dc.subjectThiazoles
dc.subjectQuinolines
dc.subjectCyclin-Dependent Kinases
dc.subjectCDC2 Protein Kinase
dc.subjectRNA, Small Interfering
dc.subjectAntineoplastic Agents
dc.subjectProtein Kinase Inhibitors
dc.subjectSurvival Analysis
dc.subjectXenograft Model Antitumor Assays
dc.subjectSignal Transduction
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectDose-Response Relationship, Drug
dc.subjectMutation
dc.subjectGenes, Lethal
dc.subjectFemale
dc.subjectProto-Oncogene Proteins p21(ras)
dc.subjectHigh-Throughput Screening Assays
dc.subjectG1 Phase Cell Cycle Checkpoints
dc.titleCDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours.
dc.typeJournal Article
dcterms.dateAccepted2016-01-27
rioxxterms.versionofrecord10.1371/journal.pone.0149099
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfPloS one
pubs.issue2
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/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-statusPublished
pubs.volume11en_US
pubs.embargo.termsNot known
icr.researchteamGene Functionen_US
dc.contributor.icrauthorLord, Christopheren
dc.contributor.icrauthorCampbell, Jamesen


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

https://creativecommons.org/licenses/by/4.0
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0