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dc.contributor.authorHolme, H
dc.contributor.authorGulati, A
dc.contributor.authorBrough, R
dc.contributor.authorFleuren, EDG
dc.contributor.authorBajrami, I
dc.contributor.authorCampbell, J
dc.contributor.authorChong, IY
dc.contributor.authorCosta-Cabral, S
dc.contributor.authorElliott, R
dc.contributor.authorFenton, T
dc.contributor.authorFrankum, J
dc.contributor.authorJones, SE
dc.contributor.authorMenon, M
dc.contributor.authorMiller, R
dc.contributor.authorPemberton, HN
dc.contributor.authorPostel-Vinay, S
dc.contributor.authorRafiq, R
dc.contributor.authorSelfe, JL
dc.contributor.authorvon Kriegsheim, A
dc.contributor.authorMunoz, AG
dc.contributor.authorRodriguez, J
dc.contributor.authorShipley, J
dc.contributor.authorvan der Graaf, WTA
dc.contributor.authorWilliamson, CT
dc.contributor.authorRyan, CJ
dc.contributor.authorPettitt, S
dc.contributor.authorAshworth, A
dc.contributor.authorStrauss, SJ
dc.contributor.authorLord, CJ
dc.date.accessioned2018-07-31T10:42:03Z
dc.date.issued2018-07-13
dc.identifier.citationScientific reports, 2018, 8 (1), pp. 10614 - ?
dc.identifier.issn2045-2322
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2226
dc.identifier.eissn2045-2322
dc.identifier.doi10.1038/s41598-018-29043-z
dc.description.abstractOsteosarcoma (OS) is an aggressive sarcoma, where novel treatment approaches are required. Genomic studies suggest that a subset of OS, including OS tumour cell lines (TCLs), exhibit genomic loss of heterozygosity (LOH) patterns reminiscent of BRCA1 or BRCA2 mutant tumours. This raises the possibility that PARP inhibitors (PARPi), used to treat BRCA1/2 mutant cancers, could be used to target OS. Using high-throughput drug sensitivity screening we generated chemosensitivity profiles for 79 small molecule inhibitors, including three clinical PARPi. Drug screening was performed in 88 tumour cell lines, including 18 OS TCLs. This identified known sensitivity effects in OS TCLs, such as sensitivity to FGFR inhibitors. When compared to BRCA1/2 mutant TCLs, OS TCLs, with the exception of LM7, were PARPi resistant, including those with previously determined BRCAness LoH profiles. Post-screen validation experiments confirmed PARPi sensitivity in LM7 cells as well as a defect in the ability to form nuclear RAD51 foci in response to DNA damage. LM7 provides one OS model for the study of PARPi sensitivity through a potential defect in RAD51-mediated DNA repair. The drug sensitivity dataset we generated in 88 TCLs could also serve as a resource for the study of drug sensitivity effects in OS.
dc.formatElectronic
dc.format.extent10614 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectCell Nucleus
dc.subjectHumans
dc.subjectOsteosarcoma
dc.subjectDNA Damage
dc.subjectBRCA1 Protein
dc.subjectBRCA2 Protein
dc.subjectDrug Screening Assays, Antitumor
dc.subjectDNA Repair
dc.subjectMutagenesis
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectRad51 Recombinase
dc.subjectHigh-Throughput Screening Assays
dc.subjectCRISPR-Cas Systems
dc.subjectDatasets as Topic
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.titleChemosensitivity profiling of osteosarcoma tumour cell lines identifies a model of BRCAness.
dc.typeJournal Article
dcterms.dateAccepted2018-07-02
rioxxterms.versionofrecord10.1038/s41598-018-29043-z
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-07-13
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfScientific reports
pubs.issue1
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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical and Translational Sarcoma
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Ashworth Collaborators
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology
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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical and Translational Sarcoma
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Ashworth Collaborators
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology
pubs.publication-statusPublished
pubs.volume8
pubs.embargo.termsNot known
icr.researchteamClinical and Translational Sarcomaen_US
icr.researchteamAshworth Collaboratorsen_US
icr.researchteamGene Functionen_US
icr.researchteamSarcoma Molecular Pathologyen_US
dc.contributor.icrauthorShipley, Janeten
dc.contributor.icrauthorSelfe, Joannaen
dc.contributor.icrauthorCampbell, Jamesen
dc.contributor.icrauthorChong, Yu-Shingen
dc.contributor.icrauthorPettitt, Stephenen
dc.contributor.icrauthorLord, Christopheren
dc.contributor.icrauthorvan der Graaf, Wilhelminaen


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