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dc.contributor.authorJenks, Andrew D
dc.contributor.authorVyse, Simon
dc.contributor.authorWong, Jocelyn P
dc.contributor.authorKostaras, Eleftherios
dc.contributor.authorKeller, Deborah
dc.contributor.authorBurgoyne, Thomas
dc.contributor.authorShoemark, Amelia
dc.contributor.authorTsalikis, Athanasios
dc.contributor.authorde la Roche, Maike
dc.contributor.authorMichaelis, Martin
dc.contributor.authorCinatl, Jindrich
dc.contributor.authorHuang, Paul H
dc.contributor.authorTanos, Barbara E
dc.date.accessioned2018-11-23T14:50:59Z
dc.date.available2018-11-23T14:50:59Z
dc.date.issued2018-06-05
dc.identifier.issn2211-1247
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285895
dc.description.abstractPrimary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications.
dc.description.sponsorshipThis research was partly funded by the Institute of Cancer Research and by grants from Sarcoma UK (to B.E.T. [14.2014] and P.H.H. [3.2014]), Kent Cancer Trust (to M.M.), Hilfe fuer Krebskranke Kinder Frankfurt e.V. and Frankfurter Stiftung fuer Krebskranke Kinder (to J.C.), CRUK-CI Core Grant (C14303/A17197), and S.H.D. Fellowship (Wellcome Trust/Royal Society [107609]) (to M.D.R.). B.E.T. was supported by an ICR fellowship.
dc.languageeng
dc.publisherElsevier
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectFGFR
dc.subjectHedgehog pathway
dc.subjectcilia
dc.subjectkinase inhibitor
dc.subjectresistance
dc.titlePrimary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer.
dc.typeArticle
prism.endingPage3055
prism.issueIdentifier10
prism.publicationDate2018
prism.publicationNameCell Reports
prism.startingPage3042
prism.volume23
dc.identifier.doi10.17863/CAM.33238
dcterms.dateAccepted2018-05-03
rioxxterms.versionofrecord10.1016/j.celrep.2018.05.016
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2018-06-05
dc.contributor.orcidde la Roche, Maike [0000-0002-0558-4119]
dc.identifier.eissn2211-1247
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (107609/Z/15/Z)
pubs.funder-project-idCancer Research UK (C14303/A17197)
cam.issuedOnline2018-06-08


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