Show simple item record

dc.contributor.authorZhang, Chien
dc.contributor.authorStockwell, Simonen
dc.contributor.authorElbanna, Mayen
dc.contributor.authorKetteler, Robinen
dc.contributor.authorFreeman, Jamieen
dc.contributor.authorAl-Lazikani, Bissanen
dc.contributor.authorEccles, Suzanneen
dc.contributor.authorDe Haven Brandon, Alexisen
dc.contributor.authorRaynaud, Florenceen
dc.contributor.authorHayes, Angelaen
dc.contributor.authorClarke, Paul Aen
dc.contributor.authorWorkman, Paulen
dc.contributor.authorMittnacht, Sibylleen
dc.date.accessioned2019-09-25T08:19:54Z
dc.date.available2019-09-25T08:19:54Z
dc.identifier.issn0950-9232
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/297081
dc.description.abstractDeregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer; yet, inhibitors against these kinases are currently used only in restricted tumour contexts. The extent to which cancers depend on CDK4/6 and the mechanisms that may undermine such dependency are poorly understood. Here, we report that signalling engaging the MET proto-oncogene receptor tyrosine kinase/focal adhesion kinase (FAK) axis leads to CDK4/6-independent CDK2 activation, involving as critical mechanistic events loss of the CDKI p21CIP1 and gain of its regulator, the ubiquitin ligase subunit SKP2. Combined inhibition of MET/FAK and CDK4/6 eliminates the proliferation capacity of cancer cells in culture, and enhances tumour growth inhibition in vivo. Activation of the MET/FAK axis is known to arise through cancer extrinsic and intrinsic cues. Our work predicts that such cues support cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases and identifies MET/FAK as a tractable route to broaden the utility of CDK4/6 inhibitor-based therapies in the clinic.
dc.description.sponsorshipThe work was supported by grants from Cancer Research UK (ref. C309/A11566, ref. C309/A8274 and ref. C309/A8992 (PW), ref. C423/A1421 and ref. C423/A15043 (SM)) and the World Cancer Research Fund (WCRF) (ref. 12-1280). CZ was supported by a Wellcome Trust studentship (ref. 094885/Z/10/Z).
dc.languageengen
dc.language.isoenen
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleSignalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases.en
dc.typeArticle
prism.endingPage5920
prism.issueIdentifier30en
prism.publicationNameOncogeneen
prism.startingPage5905
prism.volume38en
dc.identifier.doi10.17863/CAM.44128
dcterms.dateAccepted2019-05-13en
rioxxterms.versionofrecord10.1038/s41388-019-0850-2en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2019-05-13en
dc.contributor.orcidStockwell, Simon [0000-0002-3345-8945]
dc.identifier.eissn1476-5594
rioxxterms.typeJournal Article/Reviewen
cam.issuedOnline2019-07-12en


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International