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Androgen Receptor Degraders Overcome Common Resistance Mechanisms Developed During Prostate Cancer Treatment

ABSTRACT: Androgen Receptor Degraders Overcome Common Resistance Mechanisms Developed During Prostate Cancer Treatment

PROVIDER: PRJNA573618 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10162402_1.fastq.gz	Fastqsanger.gz
	SRR10162402_2.fastq.gz	Fastqsanger.gz
	SRR10162403_1.fastq.gz	Fastqsanger.gz
	SRR10162403_2.fastq.gz	Fastqsanger.gz
	SRR10162404_1.fastq.gz	Fastqsanger.gz

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Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment.

Project description:Androgen receptor (AR) antagonists, such as enzalutamide, have had a major impact on the treatment of metastatic castration-resistant prostate cancer (CRPC). However, even with the advent of AR antagonist therapies, patients continue to develop resistance, and new strategies to combat continued AR signalling are needed. Here, we develop AR degraders using PROteolysis TArgeting Chimeric (PROTAC) technology in order to determine whether depletion of AR protein can overcome mechanisms of resistance commonly associated with current AR-targeting therapies. ARD-61 is the most potent of the AR degraders and effectively induces on-target AR degradation with a mechanism consistent with the PROTAC design. Compared to clinically-approved AR antagonists, administration of ARD-61 in vitro and in vivo results in more potent anti-proliferative, pro-apoptotic effects and attenuation of downstream AR target gene expression in prostate cancer cells. Importantly, we demonstrate that ARD-61 functions in enzalutamide-resistant model systems, characterized by diverse proposed mechanisms of resistance that include AR amplification/overexpression, AR mutation, and expression of AR splice variants, such as AR-V7. While AR degraders are unable to bind and degrade AR-V7, they continue to inhibit tumor cell growth in models overexpressing AR-V7. To further explore this, we developed several isogenic prostate cell line models in which AR-V7 is highly expressed, which also failed to influence the cell inhibitory effects of AR degraders, suggesting that AR-V7 is not a functional resistance mechanism for AR antagonism. These data provide compelling evidence that full-length AR remains a prominent oncogenic driver of prostate cancers which have developed resistance to AR antagonists and highlight the clinical potential of AR degraders for treatment of CRPC.

| S-EPMC6957805 | biostudies-literature

Androgen Receptor Degraders Overcome Common Resistance Mechanisms Developed During Prostate Cancer Treatment

Project description:RNA-sequencing of VCaP and LNCaP, LNCaP-EnzR, or LNCaP AR-V7 overexpressing prostate cancer cell lines treated with AR degrader ARD-61.

2020-01-12 | GSE137833 | GEO

Effect of Selective Androgen Receptor Degraders (SARDs) on Androgen Receptor (AR) Function in MR49F (LNCaP enzalutamide-resistant) Cells

Project description:Effect of Selective Androgen Receptor Degraders (SARDs) on Androgen Receptor (AR) Function in MR49F (LNCaP enzalutamide-resistant) Cells

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Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance [WES]

Project description:SWI/SNF ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here we developed AU-24118, a first-in-class, orally bioavailable degrader of SMARCA2/4 and PBRM1. AU-24118 demonstrated tumor regression in a castration resistant model of prostate cancer which was further enhanced in combination with enzalutamide. Prostate cancer cell lines exposed to increasing doses of a SWI/SNF degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. While SMARCA4 mutations provided specific resistance to SWI/SNF degraders, ABCB1 overexpression provided broader resistance to other compounds as well as could be overcome with ABCB1 inhibition.

2024-03-15 | GSE250327 | GEO

Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance [RNA-seq]

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Targeting androgen receptor phase separation to overcome antiandrogen resistance mediated by "pharmacological condensates"

Project description:Targeting androgen receptor phase separation to overcome antiandrogen resistance mediated by "pharmacological condensates"

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HCH degraders

Project description:Degraders od hexachlorocyclohexane from environmental samples from Egypt

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Project description:PAHs and BTEX degraders Metagenome

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Electron acceptor-dependent identification of key anaerobic toluene degraders at a tar-oil contaminated aquifer by Pyro-SIP

Project description:Bioavailability of electron acceptors is probably the most limiting factor in the restoration of anoxic, contaminated environments. The oxidation of contaminants such as aromatic hydrocarbons, particularly in aquifers, often depends on the reduction of ferric iron or sulphate. We have previously detected a highly active fringe zone beneath a toluene plume at a tar-oil contaminated aquifer in Germany, where a specialized community of contaminant degraders co-dominated by Desulfobulbaceae and Geobacteraceae had established. Although on-site geochemistry links degradation to sulphidogenic processes, dominating catabolic (benzylsuccinate synthase alpha-subunit, bssA) genes detected in situ appeared more related to those of Geobacter spp. Therefore, a stable isotope probing (SIP) incubation of sediment samples with 13C7-toluene and comparative electron acceptor amendment was performed. We introduce pyrosequencing of templates from SIP microcosms as a powerful new strategy in SIP gradient interpretation (Pyro-SIP). Our results reveal the central role of Desulfobulbaceae for sulphidogenic toluene degradation in situ, and affiliate the detected bssA genes to this lineage. This, and the absence of 13C-labelled DNA of Geobacter spp. in SIP gradients preclude their relevance as toluene degraders in situ. In contrast, Betaproteobacteria related to Georgfuchsia spp. became labelled under iron-reducing conditions. Furthermore, secondary toluene degraders belonging to the Peptococcaceae detected in both treatments suggest the possibility of functional redundancy amongst anaerobic toluene degraders on site. 2 samples examined from the different electron-acceptors (sulphate or ferric iron) incubates at the time point of maximal toluene degradation.

2011-03-18 | E-GEOD-25449 | biostudies-arrayexpress

DNA-SIP ETBE degraders

Project description:Stable isotope profiling of ETBE degraders

| PRJEB52346 | ENA