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dc.contributor.authorWagner, S
dc.contributor.authorVlachogiannis, G
dc.contributor.authorDe Haven Brandon, A
dc.contributor.authorValenti, M
dc.contributor.authorBox, G
dc.contributor.authorJenkins, L
dc.contributor.authorMancusi, C
dc.contributor.authorSelf, A
dc.contributor.authorManodoro, F
dc.contributor.authorAssiotis, I
dc.contributor.authorRobinson, P
dc.contributor.authorChauhan, R
dc.contributor.authorRust, AG
dc.contributor.authorMatthews, N
dc.contributor.authorEason, K
dc.contributor.authorKhan, K
dc.contributor.authorStarling, N
dc.contributor.authorCunningham, D
dc.contributor.authorSadanandam, A
dc.contributor.authorIsacke, CM
dc.contributor.authorKirkin, V
dc.contributor.authorValeri, N
dc.contributor.authorWhittaker, SR
dc.date.accessioned2018-09-27T13:13:21Z
dc.date.issued2019-03
dc.identifier.citationOncogene, 2019, 38 (10), pp. 1717 - 1733
dc.identifier.issn0950-9232
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2887
dc.identifier.eissn1476-5594
dc.identifier.doi10.1038/s41388-018-0554-z
dc.description.abstractDespite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines. ISG expression was confirmed in patient-derived organoid models, which displayed resistance to trametinib and were resensitized by JQ1 co-treatment. In in vivo models of colorectal cancer, combination treatment significantly suppressed tumor growth. Our findings provide a novel explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Moreover, the high expression of ISGs was associated with significantly reduced survival of colorectal cancer patients. Excitingly, we have identified novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer.
dc.formatPrint-Electronic
dc.format.extent1717 - 1733
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectOrganoids
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectColorectal Neoplasms
dc.subjectAzepines
dc.subjectTriazoles
dc.subjectPyridones
dc.subjectPyrimidinones
dc.subjectInterferons
dc.subjectXenograft Model Antitumor Assays
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectDrug Synergism
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectFemale
dc.subjectProto-Oncogene Proteins p21(ras)
dc.subjectGene Regulatory Networks
dc.titleSuppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer.
dc.typeJournal Article
dcterms.dateAccepted2018-09-14
rioxxterms.versionofrecord10.1038/s41388-018-0554-z
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-03
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfOncogene
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/Molecular Cell Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Molecular Drug Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
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/Gastrointestinal Cancer Biology and Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Systems and Precision Cancer Medicine
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/Molecular Cell Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Molecular Drug Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
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/Gastrointestinal Cancer Biology and Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Systems and Precision Cancer Medicine
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume38
pubs.embargo.termsNo embargo
icr.researchteamMolecular Cell Biologyen_US
icr.researchteamCancer Pharmacology & Stress Response (CPSR)en_US
icr.researchteamMolecular Drug Resistanceen_US
icr.researchteamGastrointestinal Cancers Clinical Trialsen_US
icr.researchteamMedicine (RMH Smith Cunningham)en_US
icr.researchteamGastrointestinal Cancer Biology and Genomicsen_US
icr.researchteamSystems and Precision Cancer Medicineen_US
dc.contributor.icrauthorWhittaker, Stevenen
dc.contributor.icrauthorDe Haven Brandon, Alexisen
dc.contributor.icrauthorValenti, Melanieen
dc.contributor.icrauthorChauhan, Ritikaen
dc.contributor.icrauthorJenkins, Liamen
dc.contributor.icrauthorStarling, Naureenen
dc.contributor.icrauthorCunningham, Daviden
dc.contributor.icrauthorSadanandam, Angurajen
dc.contributor.icrauthorIsacke, Clareen
dc.contributor.icrauthorKirkin, Vladimiren
dc.contributor.icrauthorValeri, Nicolaen
dc.contributor.icrauthorEason, Katherineen


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