Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery of a Selective RXRγ Degrader WCF-598 for the Treatment of Castration-Resistant Prostate Cancer

ABSTRACT: Castration-resistant prostate cancer (CRPC) remains a significant therapeutic challenge with limited effective treatment options. We identified retinoid X receptor γ (RXRγ) as a critical regulator of CRPC cell proliferation, highlighting it as a previously unrecognized and tractable target for therapeutic intervention. However, no RXRγ-selective modulators have been reported. Herein, we utilized the PROTAC approach to develop WCF-598 as a selective RXRγ degrader, which exhibits excellent specificity over RXRα and RXRβ isoforms. WCF-598 promoted efficient RXRγ degradation through the ubiquitin–proteasome system, leading to robust anti-proliferative activity in CRPC models. In vivo, WCF-598 induced significant tumor regression in 22Rv1 xenografts-bearing mice without observable toxicity. Notably, WCF-598 also exhibited a secondary activity by degrading androgen receptor splice variant 7 (AR-V7), a clinically relevant driver of therapy resistance in CRPC. These results establish WCF-598 as a selective chemical probe for investigating the function of RXRγ in CRPC and potentially other RXRγ-related diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311340 | GEO | 2025/12/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Discovery of a Selective RXRγ Degrader WCF-598 for the Treatment of Castration-Resistant Prostate Cancer

Project description:Discovery of a Selective RXRγ Degrader WCF-598 for the Treatment of Castration-Resistant Prostate Cancer

| PRJNA1368980 | ENA

Phase separation of RXRγ drives tumor chemoresistance and represents a therapeutic target for small cell lung cancer

Project description:Small cell lung cancer (SCLC) is the most lethal type of lung cancer, characterized by limited treatment options and rapid evolution from chemosensitivity to chemoresistance. However, the mechanisms underlying this evolution remain poorly understood. Identifying the druggable drivers and developing pharmacological strategies to overcome chemoresistance are imperative. Here, we show that Retinoid X receptor γ (RXRγ) is uniquely overexpressed in chemo-resistant SCLC tumors, and that RXRγ serves as an essential factor driving chemoresistance in SCLC. RXRγ forms phase-separated droplets with LSD1 in the nucleus, which enhances RXRγ-mediated gene transcription activity and reprograms gene expression, promoting tumor stemness and metastasis, and eventually driving SCLC chemoresistance. In turn, RXRγ antagonist disrupts RXRγ-LSD1 interaction, reducing their binding to the target gene locus, markedly suppressing the expression of the RXRγ target gene network. Finally, RXRγ antagonists strongly suppress tumor growth and metastasis and restore SCLC vulnerability to chemotherapy in multiple preclinical SCLC models, without overt toxicity, in mice. Thus, these results establish RXRγ as a key player in SCLC by phase separation and as a potential therapeutic target for this deadly disease.

2024-12-31 | GSE269090 | GEO

Phase separation of RXRγ drives tumor chemoresistance and represents a therapeutic target for small cell lung cancer

2024-12-31 | GSE277738 | GEO

Phase separation of RXRγ drives tumor chemoresistance and represents a therapeutic target for small cell lung cancer [RNA-Seq]

2024-12-31 | GSE268219 | GEO

Phase separation of RXRγ drives tumor chemoresistance and represents a therapeutic target for small cell lung cancer [ChIP-Seq]

2024-12-31 | GSE268220 | GEO

Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

Project description:The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7-driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7-driven prostate tumors.

2018-05-31 | GSE99378 | GEO

Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer

Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

2023-10-11 | MTBLS8034 | MetaboLights

Cistrome analyses of AR-V7.

Project description:Although AR-V7 has been intensively studied, it remains unclear whether AR-V7 can specifically activate a distinctive transcriptional program from the full-length AR (AR-FL), and whether AR-V7 may play a role in accelerating the metastatic progression of castration-resistant PCa (CRPC). In this study, we hypothesize that AR-V7 can drive a distinct transcription program from AR-FL in CRPC condition. To test this, we used LNCaP model with inducible overexpression of AR-V7 or AR-FL to examine the effects of AR-V7 overexpression or AR-FL overexpression stimulated with DHT for 4 hours on AR-V7 or AR-FL cistromes. We also studied the effects of AR-V7 on cistromes of pioneer factor FOXA1 and active histone marker H3K27ac, and the function of phosphorylation at Ser81 on AR-V7 function in CRPC.

2024-06-05 | GSE221140 | GEO

Canonical and non-canonical regulatory roles of androgen receptor variant 7 in prostate cancer

Project description:The androgen receptor splice variant 7 (AR-V7) lacks the ligand-binding domain; is detected with increased frequency in advanced prostate cancer and is postulated to be one crucial mechanism for disease progression and therapeutic resistance to androgen deprivation in castration–resistant prostate cancer (CRPC). Targeting AR-V7 or unique downstream targets could provide novel therapeutic approaches for CRPC. Here, we report that, independent of ligand, AR-V7 binds not only to the androgen-responsive element (ARE) sites inducing canonical AR signaling but also to non-canonical target sites where ligand-stimulated full-length AR (AR-FL) does not bind. These AR-V7 “solo” binding sites are mainly found at gene promoters and are co-occupied by a zinc-finger transcription factor ZFX and the co-activator BRD4, both of which physically interact with AR-V7. Consequently, AR-V7 not only recapitulates AR-FL action without androgen but uniquely regulates transcripts correlating with AR-V7 expression in the TCGA prostate cancer cohort. Mechanistically, ZFX appears to function as a pioneer factor for AR-V7 at solo-binding sites and BRD4 inhibitors but not anti-androgens suppress AR-V7 action at solo-binding sites as well as AR-V7-dependent growth. Additionally, knockdown of ZFX, or two downstream targets uniquely co-activated by AR-V7 (ZNF32 and FZD6), also suppressed growth of AR-V7-dependent CRPC cells. AR-V7 directly activated genes differentiate tumor from normal prostate tissues and predict poor prognosis in patients. Thus AR-V7 has both canonical and non-canonical regulatory functions in CRPC, which may provide new therapeutic avenues.

2018-10-02 | GSE94013 | GEO

Transcriptome analyses of AR-V7 and ARv567es

Project description:Although AR-V7 has been intensively studied, it remains unclear whether AR-V7 and other AR splicing variants can specifically activate a distinctive transcriptional program from the full-length AR (AR-FL), and whether AR-V7 may play a role in accelerating the metastatic progression of castration-resistant PCa (CRPC). In this study, we hypothesize that AR-V7 can drive a distinct transcription program from AR-FL in CRPC condition. To test this, we used LNCaP model with inducible overexpression of AR-V7 or AR-V7-S81A to examine the transcriptional function of AR-V7 and the role of S81 phosphorylation on AR-V7 transcriptome. We also studied the endogenous AR-V7 transcriptome in CWR-22Rv1 cells using siRNA against AR-V7. Lastly, we used LNCaP model with inducible overexpression of AR-V567es to examine the AR-V567es transcriptome.

2024-06-05 | GSE221141 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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