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Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer

Authors :
Wagner, Steve
Vlachogiannis, Georgios
De Haven Brandon, Alexis
Valenti, Melanie
Box, Gary
Jenkins, Liam
Mancusi, Caterina
Self, Annette
Manodoro, Floriana
Assiotis, Ioannis
Robinson, Penny
Chauhan, Ritika
Rust, Alistair G.
Matthews, Nik
Eason, Kate
Khan, Khurum
Starling, Naureen
Cunningham, David
Sadanandam, Anguraj
Isacke, Clare M.
Kirkin, Vladimir
Valeri, Nicola
Whittaker, Steven R.
Source :
Oncogene; March 2019, Vol. 38 Issue: 10 p1717-1733, 17p
Publication Year :
2019

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.

Details

Language :
English
ISSN :
09509232 and 14765594
Volume :
38
Issue :
10
Database :
Supplemental Index
Journal :
Oncogene
Publication Type :
Periodical
Accession number :
ejs49064723
Full Text :
https://doi.org/10.1038/s41388-018-0554-z