Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

LNCAP/AR and a LnCAP/AR subline (LREX') with acquired resistance to 2nd generation antiandrogens

ABSTRACT: The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Using the LnCaP/AR xenograft model, we identified induction of glucocorticoid receptor (GR) expression as a common feature of drug resistant tumors. From a resistant xenograft tumor, we derived a GR expressing resistant subline called LREX' which maintains the resistant phenotype. mRNA expression was used to characterize resistant tissues.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51873 | GEO | 2013/12/27

SECONDARY ACCESSION(S): PRJNA225675

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

LNCAP/AR and a LnCAP/AR subline (LREX') with acquired resistance to 2nd generation antiandrogens

Project description:The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Using the LnCaP/AR xenograft model, we identified induction of glucocorticoid receptor (GR) expression as a common feature of drug resistant tumors. From a resistant xenograft tumor, we derived a GR expressing resistant subline called LREX' which maintains the resistant phenotype. mRNA expression was used to characterize resistant tissues. LnCaP/AR cells were injected into castrate mice and tumors were established. Mice were then treated with vehicle (Con), 4 days of anti-androgen (ARN-509 10mgkg), or were maintained on anti-androgen (10mg/kg ARN-509 or enzalutamide) until emergence of resistance. Resistant tissues continued to be exposed to anti-androgen through time of harvest. LREX' (LnCaP/AR Resistant to Enzalutamide Xenograft Derived) was derived from an enzalutamide resistant xenograft and was re-injected into castrate mice undergoing continual treatment with enzalutamide. The GR probe on the Illumina array failed to detect GR expression. Therefore, GR expression as determined by qPCR is annotated separately. Of the 10 control tissues, 8 were analyzed twice (technical duplicates annotated as A and B).

2013-12-27 | E-GEOD-51873 | biostudies-arrayexpress

Androgen and Glucocorticoid stimulation of LREX' cells in vitro

2013-12-27 | E-GEOD-51871 | biostudies-arrayexpress

Androgen and Glucocorticoid stimulation of LREX' cells in vitro

2013-12-27 | GSE51871 | GEO

Linking prostate cancer cell AR heterogeneity to distinct castration and Enzalutamide responses

Project description:Molecular mechanisms underlying resistance to androgen deprivation therapy (ADT) and, in particular, to antiandrogen Enzalutamide, in treating castration-resistant prostate cancer (CRPC), remain incompletely understood. Through screening >120 CRPC patient samples, we observed 3 expression patterns of androgen receptor (AR) protein: primarily nuclear (nuc-AR), mixed nuclear/cytoplasmic expression (nuc/cyto-AR), and low/no expression (AR-/lo). Xenograft CRPC modeling in 4 models (i.e., LNCaP, VCaP, LAPC4, and LAPC9) recapitulated the 3 AR expression patterns in castration-resistant tumors developed from parental androgen-dependent tumors. Strikingly, although the 3 CRPC models that retained AR expression (LNCaP, VCaP, and LAPC4) responded, to different levels and in different kinetics, to Enzalutamide, the AR-/lo LAPC9 CRPC was completely refractory to Enzalutamide. By combining whole-genome RNA-Seq and biochemical analyses together with experimental combinatorial therapy in the LNCaP and LAPC9 models, we identified BCL-2 as a critical therapeutic target in both AR+/hi and AR-/lo, Enzalutamide-resistant CRPC models.

2018-08-01 | GSE88752 | GEO

Gene expression analysis of bladder cancer cell line, its BCG resistant and AR knockdown subline.

Project description:BCG resistant and AR konckdown subline from UMUC3 were compared with the original cell line.

2021-04-01 | GSE148322 | GEO

Dexamethasone treatment of VCaP prostate cells

Project description:The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. We identified glucocorticoid receptor (GR) activity as modulator of enzalutamite sensitivity in the VCaP prostate cancer cell line. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance whereas a GR antagonist restored sensitivity. These expression profiling data demonstrate that GR transcriptional activity overlaps with that of AR in the VCAP model. VCAP cells growing in complete media were treated with the indicated drugs in biological triplicates for 24 hours prior to harvest.

2013-12-27 | E-GEOD-51872 | biostudies-arrayexpress

Dexamethasone treatment of VCaP prostate cells

2013-12-27 | GSE51872 | GEO

Analysis of gene expression (RNAseq) from shTP53:RB1 LNCaP/AR cell lines

Project description:Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. Here we show, using in vitro and in vivo prostate cancer models, that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR) dependent luminal epithelial cells to AR independent basal-like cells. This lineage plasticity is enabled by loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2 and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.

2017-01-06 | GSE89226 | GEO

Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer

Project description:In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.

2017-09-11 | GSE103449 | GEO

Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer [RNA-seq]

Project description:Next generation androgen receptor (AR) signaling inhibitors have significantly improved the survival of men with metastatic castration-resistant prostate cancer (mCPRC) but resistance remains a problem. Genomic alterations at the AR locus are present in ~50% of mCRPC patients, typically in association with large numbers of copy number gains and losses across the genome. To explore the functional consequences of these copy number alterations, we screened an shRNA library targeting all genes deleted in prostate cancer (the prostate cancer deletome: 4380 shRNAs targeting 730 genes) for next generation antiandrogen resistance using a clinically-validated model of enzalutamide-sensitive, AR-driven mCRPC LNCaP/AR. The Chromatin helicase DNA-binding factor (CHD1) scored as a top candidate and was validated in vitro and in vivo using multiple independent shRNAs and CRISPR guides. Mechanistically, CHD1 loss led to global changes in open and closed chromatin (ATAC-seq) as well as downregulation of canonical AR target genes upon the challenge of antiandrogen, despite robust AR expression. Integrative analysis of ATAC- and RNA-seq changes following CHD1 deletion identified 23 candidate transcription factor drivers of enzalutamide resistance. CRISPR-based unbiased functional screening identified 4 of these drivers may drive the AR-independent resistance, including glucocorticoid receptor (GR), BRN2, NR2F1 and TBX2. Genetic studies further establish that CHD1 loss confers antiandrogen resistance by converting mCRPC cells from AR-dependence to GR-dependence in one of the resistant LNCaP/AR clone. Thus, CHD1 functions as a molecular tuner to regulate chromatin plasticity and maintain oncogenic AR signaling, as well as AR dependency.

2020-03-26 | GSE126917 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data