Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer.
Date
2019-03-07ICR Author
Author
Wagner, S
Vlachogiannis, G
De Haven Brandon, A
Valenti, M
Box, G
Jenkins, L
Mancusi, C
Self, A
Manodoro, F
Assiotis, I
Robinson, P
Chauhan, R
Rust, AG
Matthews, N
Eason, K
Khan, K
Starling, N
Cunningham, D
Sadanandam, A
Isacke, CM
Kirkin, V
Valeri, N
Whittaker, SR
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Organoids
Cell Line, Tumor
Animals
Humans
Mice
Colorectal Neoplasms
Azepines
Triazoles
Pyridones
Pyrimidinones
Interferons
Xenograft Model Antitumor Assays
Gene Expression Regulation, Neoplastic
Drug Synergism
Drug Resistance, Neoplasm
Mutation
Female
Proto-Oncogene Proteins p21(ras)
Gene Regulatory Networks
Research team
Molecular Cell Biology
Cancer Pharmacology & Stress Response (CPSR)
Molecular Drug Resistance
Gastrointestinal Cancers Clinical Trials
Medicine (RMH Smith Cunningham)
Gastrointestinal Cancer Biology and Genomics
Systems and Precision Cancer Medicine
Language
eng
Date accepted
2018-09-14
License start date
2019-03
Citation
Oncogene, 2019, 38 (10), pp. 1717 - 1733
Publisher
NATURE PUBLISHING GROUP