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dc.contributor.authorLampis, A
dc.contributor.authorCarotenuto, P
dc.contributor.authorVlachogiannis, G
dc.contributor.authorCascione, L
dc.contributor.authorHedayat, S
dc.contributor.authorBurke, R
dc.contributor.authorClarke, P
dc.contributor.authorBosma, E
dc.contributor.authorSimbolo, M
dc.contributor.authorScarpa, A
dc.contributor.authorYu, S
dc.contributor.authorCole, R
dc.contributor.authorSmyth, E
dc.contributor.authorMateos, JF
dc.contributor.authorBegum, R
dc.contributor.authorHezelova, B
dc.contributor.authorEltahir, Z
dc.contributor.authorWotherspoon, A
dc.contributor.authorFotiadis, N
dc.contributor.authorBali, MA
dc.contributor.authorNepal, C
dc.contributor.authorKhan, K
dc.contributor.authorStubbs, M
dc.contributor.authorHahne, JC
dc.contributor.authorGasparini, P
dc.contributor.authorGuzzardo, V
dc.contributor.authorCroce, CM
dc.contributor.authorEccles, S
dc.contributor.authorFassan, M
dc.contributor.authorCunningham, D
dc.contributor.authorAndersen, JB
dc.contributor.authorWorkman, P
dc.contributor.authorValeri, N
dc.contributor.authorBraconi, C
dc.date.accessioned2017-11-22T16:13:31Z
dc.date.issued2018-03
dc.identifier.citationGastroenterology, 2018, 154 (4), pp. 1066 - 1079.e5
dc.identifier.issn0016-5085
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/934
dc.identifier.eissn1528-0012en_US
dc.identifier.doi10.1053/j.gastro.2017.10.043en_US
dc.description.abstractBACKGROUND & AIMS:Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors. METHODS:We performed a high-throughput screen of 484 small-molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice. RESULTS:Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of patient-derived organoids to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21. CONCLUSIONS:miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for the treatment of CCA and miRNA21 might be a marker of sensitivity to these agents.
dc.formatPrint-Electronic
dc.format.extent1066 - 1079.e5
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectOrganoids
dc.subjectCell Line, Tumor
dc.subjectTumor Cells, Cultured
dc.subjectAnimals
dc.subjectMice, Inbred NOD
dc.subjectHumans
dc.subjectMice, SCID
dc.subjectCholangiocarcinoma
dc.subjectBile Duct Neoplasms
dc.subjectIsocitrate Dehydrogenase
dc.subjectNuclear Proteins
dc.subjectTranscription Factors
dc.subjectMicroRNAs
dc.subjectAntineoplastic Agents
dc.subjectXenograft Model Antitumor Assays
dc.subjectTransfection
dc.subjectSignal Transduction
dc.subjectCell Survival
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectDose-Response Relationship, Drug
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectTime Factors
dc.subjectHSP90 Heat-Shock Proteins
dc.subjectHSP40 Heat-Shock Proteins
dc.titleMIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma.
dc.typeJournal Article
dcterms.dateAccepted2017-10-27
rioxxterms.funderThe Institute of Cancer Research
rioxxterms.identifier.projectUnspecified
rioxxterms.versionofrecord10.1053/j.gastro.2017.10.043
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-03en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfGastroenterology
pubs.issue4
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/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Evolutionary Genomics & Modelling
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
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/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Evolutionary Genomics & Modelling
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.publication-statusPublished
pubs.volume154en_US
pubs.embargo.termsNot known
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamMedicine (RMH Smith Cunningham)en_US
icr.researchteamEvolutionary Genomics & Modellingen_US
icr.researchteamFunctional Genomicsen_US
icr.researchteamGastrointestinal Cancer Biology and Genomicsen_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorBraconi, Chiaraen
dc.contributor.icrauthorSmyth, Lizzyen
dc.contributor.icrauthorHahne, Jensen
dc.contributor.icrauthorBurke, Rosemaryen
dc.contributor.icrauthorLampis, Andreaen
dc.contributor.icrauthorCarotenuto, Pietroen
dc.contributor.icrauthorHedayat-Husseyin, Somaiehen
dc.contributor.icrauthorClarke, Paulen
dc.contributor.icrauthorCunningham, Daviden
dc.contributor.icrauthorValeri, Nicolaen
dc.contributor.icrauthorWorkman, Paulen
dc.contributor.icrauthorMarsden,en


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