dc.contributor.author | Wagner, S | |
dc.contributor.author | Vlachogiannis, G | |
dc.contributor.author | De Haven Brandon, A | |
dc.contributor.author | Valenti, M | |
dc.contributor.author | Box, G | |
dc.contributor.author | Jenkins, L | |
dc.contributor.author | Mancusi, C | |
dc.contributor.author | Self, A | |
dc.contributor.author | Manodoro, F | |
dc.contributor.author | Assiotis, I | |
dc.contributor.author | Robinson, P | |
dc.contributor.author | Chauhan, R | |
dc.contributor.author | Rust, AG | |
dc.contributor.author | Matthews, N | |
dc.contributor.author | Eason, K | |
dc.contributor.author | Khan, K | |
dc.contributor.author | Starling, N | |
dc.contributor.author | Cunningham, D | |
dc.contributor.author | Sadanandam, A | |
dc.contributor.author | Isacke, CM | |
dc.contributor.author | Kirkin, V | |
dc.contributor.author | Valeri, N | |
dc.contributor.author | Whittaker, SR | |
dc.date.accessioned | 2018-09-27T13:13:21Z | |
dc.date.issued | 2019-03-07 | |
dc.identifier.citation | Oncogene, 2019, 38 (10), pp. 1717 - 1733 | |
dc.identifier.issn | 0950-9232 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/2887 | |
dc.identifier.eissn | 1476-5594 | |
dc.identifier.doi | 10.1038/s41388-018-0554-z | |
dc.description.abstract | Despite 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.format | Print-Electronic | |
dc.format.extent | 1717 - 1733 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Organoids | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Colorectal Neoplasms | |
dc.subject | Azepines | |
dc.subject | Triazoles | |
dc.subject | Pyridones | |
dc.subject | Pyrimidinones | |
dc.subject | Interferons | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Drug Synergism | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Mutation | |
dc.subject | Female | |
dc.subject | Proto-Oncogene Proteins p21(ras) | |
dc.subject | Gene Regulatory Networks | |
dc.title | Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-09-14 | |
rioxxterms.versionofrecord | 10.1038/s41388-018-0554-z | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-03 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncogene | |
pubs.issue | 10 | |
pubs.notes | No 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-status | Published | |
pubs.volume | 38 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Molecular Cell Biology | |
icr.researchteam | Cancer Pharmacology & Stress Response (CPSR) | |
icr.researchteam | Molecular Drug Resistance | |
icr.researchteam | Gastrointestinal Cancers Clinical Trials | |
icr.researchteam | Medicine (RMH Smith Cunningham) | |
icr.researchteam | Gastrointestinal Cancer Biology and Genomics | |
icr.researchteam | Systems and Precision Cancer Medicine | |
dc.contributor.icrauthor | De Haven Brandon, Alexis | |
dc.contributor.icrauthor | Valenti, Melanie | |
dc.contributor.icrauthor | Jenkins, Liam | |
dc.contributor.icrauthor | Chauhan, Ritika | |
dc.contributor.icrauthor | Eason, Katherine | |
dc.contributor.icrauthor | Isacke, Clare | |
dc.contributor.icrauthor | Kirkin, Vladimir | |
dc.contributor.icrauthor | Valeri, Nicola | |
dc.contributor.icrauthor | Whittaker, Steven | |