Dopamine Receptor D5 is a Modulator of Tumor Response to Dopamine Receptor D2 Antagonism.
Antineoplastic Agents
/ pharmacology
Biomarkers
Cell Line, Tumor
Cell Survival
/ drug effects
Dopamine D2 Receptor Antagonists
/ pharmacology
Drug Resistance
/ genetics
Gene Expression
Humans
Imidazoles
/ pharmacology
Immunohistochemistry
Magnetic Resonance Imaging
Neoplasm Grading
Neoplasm Staging
Neoplasms
/ diagnosis
Prognosis
Protein Binding
Pyridines
/ pharmacology
Pyrimidines
/ pharmacology
Receptors, Dopamine D2
/ genetics
Receptors, Dopamine D5
/ chemistry
Signal Transduction
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 04 2019
01 04 2019
Historique:
received:
08
08
2018
revised:
17
10
2018
accepted:
10
12
2018
pubmed:
19
12
2018
medline:
12
5
2020
entrez:
19
12
2018
Statut:
ppublish
Résumé
Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that opposes DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201. The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in >1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. IHC staining of DRD2/DRD5 was performed on tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies. DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.
Identifiants
pubmed: 30559168
pii: 1078-0432.CCR-18-2572
doi: 10.1158/1078-0432.CCR-18-2572
pmc: PMC7259201
mid: NIHMS1517324
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers
0
Dopamine D2 Receptor Antagonists
0
Imidazoles
0
Pyridines
0
Pyrimidines
0
Receptors, Dopamine D2
0
Receptors, Dopamine D5
137750-35-7
TIC10 compound
9U35A31JAI
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
2305-2313Subventions
Organisme : NCI NIH HHS
ID : R01 CA173453
Pays : United States
Organisme : NCI NIH HHS
ID : R44 CA192427
Pays : United States
Organisme : Intramural NIH HHS
ID : Z99 CA999999
Pays : United States
Informations de copyright
©2018 American Association for Cancer Research.
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