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dc.contributor.authorFrankum, J
dc.contributor.authorMoudry, P
dc.contributor.authorBrough, R
dc.contributor.authorHodny, Z
dc.contributor.authorAshworth, A
dc.contributor.authorBartek, J
dc.contributor.authorLord, CJ
dc.date.accessioned2016-09-14T09:36:06Z
dc.date.issued2015-05
dc.identifier.citationOncotarget, 2015, 6 (13), pp. 10746 - 10758
dc.identifier.issn1949-2553
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/108
dc.identifier.eissn1949-2553
dc.identifier.doi10.18632/oncotarget.3628
dc.description.abstractBased on a series of basic, preclinical and clinical studies, the Poly (ADP-ribose) Polymerase 1 (PARP1) inhibitor, olaparib, has recently been approved for use in ovarian cancer patients with BRCA1 or BRCA2 mutations. By identifying novel predictive biomarkers of tumour cell sensitivity to olaparib, it is possible that the utility of PARP inhibitors could be extended beyond this patient subgroup. Many of the known genetic determinants of PARP inhibitor response have key roles in DNA damage response (DDR) pathways. Although protein ubiquitylation is known to play an important role in regulating the DDR, the exact mechanisms by which this occurs are not fully understood. Using two parallel RNA interference-based screening approaches, we identified the E3 ubiquitin ligase, CBLC, as a candidate biomarker of response to olaparib. We validated this observation by demonstrating that silencing of CBLC causes increased sensitivity to olaparib in breast cancer cell line models and that defective homologous recombination (HR) DNA repair is the likely cause. This data provides an example of how defects in the ubiquitin machinery have the potential to influence the response of tumour cells to PARP inhibitors.
dc.formatPrint
dc.format.extent10746 - 10758
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectPiperazines
dc.subjectPhthalazines
dc.subjectPoly(ADP-ribose) Polymerases
dc.subjectBRCA2 Protein
dc.subjectTransfection
dc.subjectSignal Transduction
dc.subjectCell Survival
dc.subjectDNA Repair
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectRNA Interference
dc.subjectProtein Processing, Post-Translational
dc.subjectRecombination, Genetic
dc.subjectDose-Response Relationship, Drug
dc.subjectTime Factors
dc.subjectFemale
dc.subjectProto-Oncogene Proteins c-cbl
dc.subjectUbiquitination
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.subjectPoly (ADP-Ribose) Polymerase-1
dc.titleComplementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity.
dc.typeJournal Article
dcterms.dateAccepted2015-02-20
rioxxterms.versionofrecord10.18632/oncotarget.3628
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2015-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfOncotarget
pubs.issue13
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.volume6
pubs.embargo.termsNot known
icr.researchteamGene Functionen_US
dc.contributor.icrauthorLord, Christopheren


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