Identification of drivers and therapeutic vulnerabilities in anti-androgen resistant prostate cancer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE130534 | GEO | 2019/09/26
REPOSITORIES: GEO
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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
Project description: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.
2019-12-31 | GSE133119 | GEO
Project description:Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) â?? the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. RNA-seq profiles of prostate cancer cell lines to understand gene expression associated with enzalutamide treatment
2016-06-10 | E-GEOD-69896 | biostudies-arrayexpress
Project description:Enzalutamide (formerly MDV3100 and available commercially as Xtandi), a novel androgen receptor (AR) signaling inhibitor, blocks the growth of castration-resistant prostate cancer (CRPC) in cellular model systems and was shown in a clinical study to increase survival in patients with metastatic CRPC. Enzalutamide inhibits multiple steps of AR signaling: (1) binding of androgens to AR, (2) AR nuclear translocation, and (3) association of AR with DNA. Here we used Affymetrix human genome microarray technology to investigate the global programme of gene expression of LNCaP cells in response to enzalutamide alone and in the context of DHT-stimulated androgen receptor gene expression. LNCaP cells were grown in RPMI 1640 supplemented with 5% hormone depleted FBS and treated with vehicle (control sample) , DHT (100 nM), enzalutamide (1 or 10 M-BM-5M) or DHT (100 nM) plus enzalutamide (1 or 10 M-BM-5M)for 16 hours for RNA extraction and hybridization. Each condition was done in triplicate.
2013-04-01 | E-GEOD-44905 | biostudies-arrayexpress
Project description:In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various stages of the disease. However, therapy resistance inevitably occurs and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. In addition, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 – from inactive chromatin binding sites towards active cis-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian rhythm core component ARNTL. Post-treatment ARNTL levels associated with poor outcome, and ARNTL suppression decreased cell growth in vitro. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy, and revealed an acquired dependency on circadian regulator ARNTL, a novel candidate therapeutic target.
2022-10-14 | PXD032041 | Pride
Project description:Advanced bladder cancer is treated mainly with gemcitabine and cisplatin, but most patients eventually become resistance to these chemotherapeutic agents. Androgen receptor (AR) signaling has been implicated in bladder cancer as well as other types of cancer including prostate cancer. In the present study, we showed the expression and role of AR in gemcitabine-resistant bladder cancer cells and examined the potential of enzalutamide, an AR inhibitor, as a therapeutic for the chemoresistance. First of all, we established gemcitabine-resistant T24 cells (T24GR) from T24 bladder cancer cells and performed gene expression profiling and network analysis, which revealed increased AR expression and AR-related gene network in T24GR cells. Quantitative RT-PCR and Western blot analysis confirmed increased expression of AR in T24GR cells compared with parental T24 cells, which was associated with more potent transcriptional activity of AR in T24GR cells. The number of AR gene copy in T24GR cells was twice as many as that of T24 cells. Knockdown of AR expression by siRNA resulted in inhibition of proliferation of T24GR cells. Cell culture in charcoal-stripped serum and treatment with enzalutamide also inhibited growth of T24GR cells, which was accompanied by cell cycle arrest. Lastly, the AR transcriptional activity was found to be reduced in T24GR cells by enzalutamide treatment. Our results suggest that blockade of AR signaling by enzalutamide might be effective for patients with advanced gemcitabine-resistant bladder cancer with increased AR expression.
2016-11-30 | GSE77883 | GEO
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
Project description:The goal of this study was to determine how androgen receptor inhibition alters transcriptional programs in prostate cancer cells. LNCaP prostate cancer cells were grown in 10% charcoal-stripped serum (CSS) supplemented with 0.5 nanomolar dihydrotestosterone (DHT), in CSS without DHT modeling castration, with CSS + DHT but in the presence of 10 micromolar enzalutamide, or in CSS without DHT (castrated) and in the presence of enzalutamide for 72 hours. Analysis shows that androgen receptor target genes are reduced with castration, enzalutamide or the combination of castration + enzalutamide.
2022-05-12 | GSE202755 | GEO
Project description:Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) – the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation.
2016-06-10 | GSE69896 | GEO
Project description:Background. Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor protein which lacks the ligand-binding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of AR-V7 in circulating tumor cells (CTCs) from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. Methods. We used quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with metastatic castration-resistant prostate cancer initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status and PSA response rates, PSA-progression-free-survival (PSA-PFS), clinical/radiographic-progression-free-survival (PFS), and overall survival (OS). Multivariable Cox regression analyses were performed to determine the independent effect of AR-V7 status on clinical outcomes. Results. Thirty-one enzalutamide-treated patients and thirty-one abiraterone-treated patients were enrolled, of which 38.7% and 19.4% had detectable AR-V7 from CTCs, respectively. Among men receiving enzalutamide, AR-V7–positive patients had inferior PSA response rates (0% vs 52.6%, P=0.004), PSA-PFS (median: 1.4 vs 6.0 months, P<0.001), PFS (median: 2.1 vs 6.1 months, P<0.001), and OS (median: 5.5 months vs not reached, P=0.002) compared to AR-V7–negative patients. Similarly, among men receiving abiraterone, AR-V7–positive patients had inferior PSA response rates (0% vs 68.0%, P=0.004), PSA-PFS (median: 1.3 months vs not reached, P<0.001), PFS (median: 2.3 months vs not reached, P<0.001), and OS (median: 10.6 months vs not reached, P=0.006). The negative prognostic impact of AR-V7 was maintained after adjusting for full-length-AR expression. Conclusions. Detection of AR-V7 in CTCs from patients with castration-resistant prostate cancer is associated with resistance to enzalutamide and abiraterone. A total of four metastatic castration-resistant prostate tumor samples from four patients were subjected to RNA-seq. Two samples were positive for androgen receptor splice variant 7 and the other two were negative for this variant.
2014-09-03 | E-GEOD-56701 | biostudies-arrayexpress