Ontology type: schema:ScholarlyArticle Open Access: True
2018-10-23
AUTHORSSteve Wagner, Georgios Vlachogiannis, Alexis De Haven Brandon, Melanie Valenti, Gary Box, Liam Jenkins, Caterina Mancusi, Annette Self, Floriana Manodoro, Ioannis Assiotis, Penny Robinson, Ritika Chauhan, Alistair G. Rust, Nik Matthews, Kate Eason, Khurum Khan, Naureen Starling, David Cunningham, Anguraj Sadanandam, Clare M. Isacke, Vladimir Kirkin, Nicola Valeri, Steven R. Whittaker
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. More... »
PAGES1717-1733
http://scigraph.springernature.com/pub.10.1038/s41388-018-0554-z
DOIhttp://dx.doi.org/10.1038/s41388-018-0554-z
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PUBMEDhttps://www.ncbi.nlm.nih.gov/pubmed/30353166
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]Download the RDF metadata as: json-ld nt turtle xml License info
JSON-LD is a popular format for linked data which is fully compatible with JSON.
curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/s41388-018-0554-z'
N-Triples is a line-based linked data format ideal for batch operations.
curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/s41388-018-0554-z'
Turtle is a human-readable linked data format.
curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/s41388-018-0554-z'
RDF/XML is a standard XML format for linked data.
curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/s41388-018-0554-z'
This table displays all metadata directly associated to this object as RDF triples.
424 TRIPLES
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121 URIs
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26 BLANK NODES