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dc.contributor.authorChong, IY
dc.contributor.authorAronson, L
dc.contributor.authorBryant, H
dc.contributor.authorGulati, A
dc.contributor.authorCampbell, J
dc.contributor.authorElliott, R
dc.contributor.authorPettitt, S
dc.contributor.authorWilkerson, P
dc.contributor.authorLambros, MB
dc.contributor.authorReis-Filho, JS
dc.contributor.authorRamessur, A
dc.contributor.authorDavidson, M
dc.contributor.authorChau, I
dc.contributor.authorCunningham, D
dc.contributor.authorAshworth, A
dc.contributor.authorLord, CJ
dc.date.accessioned2017-08-29T11:06:16Z
dc.date.issued2018-10
dc.identifier.citationGut, 2018, 67 (10), pp. 1780 - 1792
dc.identifier.issn0017-5749
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/796
dc.identifier.eissn1468-3288
dc.identifier.doi10.1136/gutjnl-2017-314408
dc.description.abstractObjective Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited.Design To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets.Results By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G 1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer.Conclusions BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway (NCT02884453).Trial registration number NCT02884453; Pre-results.
dc.formatPrint-Electronic
dc.format.extent1780 - 1792
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectEsophageal Neoplasms
dc.subjectPyrazoles
dc.subjectPyrimidines
dc.subjectReceptor, erbB-2
dc.subjectProto-Oncogene Proteins c-myc
dc.subjectAntineoplastic Agents
dc.subjectXenograft Model Antitumor Assays
dc.subjectPharmacogenetics
dc.subjectSignal Transduction
dc.subjectRNA Interference
dc.subjectDrug Discovery
dc.subjectPharmacogenomic Testing
dc.titleMapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer.
dc.typeOther
rioxxterms.versionofrecord10.1136/gutjnl-2017-314408
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-10
rioxxterms.typeOther
dc.relation.isPartOfGut
pubs.issue10
pubs.notesNo embargo
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/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/Ashworth Collaborators
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
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/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/Ashworth Collaborators
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume67
pubs.embargo.termsNo embargo
icr.researchteamMedicine (RMH Smith Cunningham)en_US
icr.researchteamAshworth Collaboratorsen_US
icr.researchteamGene Functionen_US
dc.contributor.icrauthorChong, Yu-Shingen
dc.contributor.icrauthorLord, Christopheren
dc.contributor.icrauthorChau, Ianen
dc.contributor.icrauthorCunningham, Daviden
dc.contributor.icrauthorCampbell, Jamesen
dc.contributor.icrauthorPettitt, Stephenen


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