Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer.
Animals
Azepines
/ administration & dosage
Cell Line, Tumor
Colorectal Neoplasms
/ drug therapy
Drug Resistance, Neoplasm
/ drug effects
Drug Synergism
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Gene Regulatory Networks
/ drug effects
Humans
Interferons
/ metabolism
Mice
Mutation
Organoids
/ drug effects
Proto-Oncogene Proteins p21(ras)
/ genetics
Pyridones
/ administration & dosage
Pyrimidinones
/ administration & dosage
Triazoles
/ administration & dosage
Xenograft Model Antitumor Assays
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
13
03
2018
accepted:
14
09
2018
revised:
14
09
2018
pubmed:
26
10
2018
medline:
15
5
2019
entrez:
25
10
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30353166
doi: 10.1038/s41388-018-0554-z
pii: 10.1038/s41388-018-0554-z
pmc: PMC6462854
doi:
Substances chimiques
(+)-JQ1 compound
0
Azepines
0
KRAS protein, human
0
Pyridones
0
Pyrimidinones
0
Triazoles
0
trametinib
33E86K87QN
Interferons
9008-11-1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1717-1733Commentaires et corrections
Type : ErratumIn
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