Inhibition of NF-κB-Dependent Signaling Enhances Sensitivity and Overcomes Resistance to BET Inhibition in Uveal Melanoma.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Cell Proliferation
Drug Resistance, Neoplasm
Drug Synergism
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Liver Neoplasms
/ drug therapy
Melanoma
/ drug therapy
Mice
Mice, Nude
NF-kappa B
/ antagonists & inhibitors
Proteins
/ antagonists & inhibitors
Tumor Cells, Cultured
Uveal Neoplasms
/ drug therapy
Xenograft Model Antitumor Assays
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 05 2019
01 05 2019
Historique:
received:
31
10
2018
revised:
29
01
2019
accepted:
13
03
2019
pubmed:
20
3
2019
medline:
8
2
2020
entrez:
20
3
2019
Statut:
ppublish
Résumé
Bromodomain and extraterminal protein inhibitors (BETi) are epigenetic therapies aimed to target dysregulated gene expression in cancer cells. Despite early successes of BETi in a range of malignancies, the development of drug resistance may limit their clinical application. Here, we evaluated the mechanisms of BETi resistance in uveal melanoma, a disease with little treatment options, using two approaches: a high-throughput combinatorial drug screen with the clinical BET inhibitor PLX51107 and RNA sequencing of BETi-resistant cells. NF-κB inhibitors synergistically sensitized uveal melanoma cells to PLX51107 treatment. Furthermore, genes involved in NF-κB signaling were upregulated in BETi-resistant cells, and the transcription factor CEBPD contributed to the mechanism of resistance. These findings suggest that inhibitors of NF-κB signaling may improve the efficacy of BET inhibition in patients with advanced uveal melanoma. SIGNIFICANCE: These findings provide evidence that inhibitors of NF-κB signaling synergize with BET inhibition in
Identifiants
pubmed: 30885979
pii: 0008-5472.CAN-18-3177
doi: 10.1158/0008-5472.CAN-18-3177
pmc: PMC6643281
mid: NIHMS1037197
doi:
Substances chimiques
Antineoplastic Agents
0
NF-kappa B
0
Proteins
0
bromodomain and extra-terminal domain protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2415-2425Subventions
Organisme : NCI NIH HHS
ID : R01 CA160495
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA186686
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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