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Series GSE133119 Query DataSets for GSE133119
Status Public on Dec 31, 2019
Title Effect of Selective Androgen Receptor Degraders (SARDs) on Androgen Receptor (AR) Function in MR49F (LNCaP enzalutamide-resistant) Cells
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand binding domain (LBD)-binding antagonists, are inactivated by common resistance -mechanisms. It is important to develop next-generation mechanistically-distinct drugs to treat castration- and drug- resistant prostate cancers. Here, we describe a second-generation AR pan-antagonist (UT-34) that degrades the AR and AR splice variants. UT-34 inhibits the wild-type and LBD mutant ARs comparably and inhibits the in vitro proliferation and in vivo growth of enzalutamide-sensitive and resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist, enzalutamide, and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with G-Protein Coupled Receptor, kinase, and nuclear receptor family members. Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug.
MR49F cells (n=3-4/group) were maintained in charcoal-stripped serum containing medium for 48 hours and treated with vehicle, 0.1 nM R1881, or 10 uM of UT-34 in combination with 0.1 nM R1881. Twenty four hours after treatment, the cells were harvested, RNA was isolated and expression of genes was measured using microarray (Affymetrix Clarion S)
UT-34 is a selective androgen receptor degrader that degrades and antagonizes the AR. UT-34 binds to the AF-1 domain of the AR and degrades the AR through ubiquitin proteasome pathways. The transcriptome study was performed to evaluate the ability of UT-34 to antagonize the enzalutamide-resistant AR function.
 
Overall design MR49F cells were maintained in charcoal-stripped serum containing medium for 48 hours and treated with vehicle, 0.1 nM R1881, or 10 uM of UT-34 in combination with 0.1 nM R1881. Twenty four hours after treatment, the cells were harvested, RNA was isolated and expression of genes was measured using microarray (Affymetrix Clarion S)
 
Contributor(s) Narayanan R
Citation missing Has this study been published? Please login to update or notify GEO.
Submission date Jun 20, 2019
Last update date Jan 02, 2020
Contact name Daniel Lee Johnson
E-mail(s) djohn166@uthsc.edu
Phone 9014483743
Organization name UTHSC
Department Molecular Informatics Core
Street address 71 S Manassas
City Memphis
State/province Tennessee
ZIP/Postal code 38163
Country USA
 
Platforms (1)
GPL23159 [Clariom_S_Human] Affymetrix Clariom S Assay, Human (Includes Pico Assay)
Samples (10)
GSM3900370 10a vehicle
GSM3900371 10b vehicle
GSM3900372 10c vehicle
Relations
BioProject PRJNA549970

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE133119_RAW.tar 10.7 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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