Transcriptional profiles of castration resistant prostate cancer cells treated with ITRI-148 PROTAC targeting AR and AR-V7
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE297577 | GEO | 2025/11/13
REPOSITORIES: GEO
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Project description:The purpose of this study was to characterize the downstream transcriptomic effects of ARVib-mediated degradation of AR/AR-V7, particularly in attenuating AR/AR-V7 target gene expression in prostate cancer cells. Towards this goal, next-generation sequencing (NGS)-based gene expression profiling (RNA-Sequencing; RNA-Seq) was performed on castration-resistant prostate cancer (CRPC) C4-2B MDVR cells that were treated with vehicle control or one of the AR/AR-V7 inhibitors (ARVib), ARVib-7 or ARVib-31.
2021-08-22 | GSE158556 | 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
Project description:The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for new therapeutic strategies targeting key resistant drivers such as AR variants like AR-V7 and steroidogenic enzymes such as AKR1C3 to overcome drug resistance and improve outcomes for patients with advanced prostate cancer. Here we have designed, synthesized, and characterized a novel class of LX compounds targeting both the AR/AR-Variants and AKR1C3 pathways. Molecular docking and in vitro studies demonstrated that LX compounds bind to the AKR1C3 active sites and inhibit AKR1C3 enzymatic activity. LX compounds were also shown to reduce AR/AR-V7 expression and inhibit their target gene signaling. LX1 inhibited the conversion of androstenedione into testosterone in tumor-based ex vivo enzyme assays. In addition, LX1 inhibited the growth of cells resistant to antiandrogens including enzalutamide, abiraterone, apalutamide and darolutamide in vitro. A synergistic effect was observed when LX1 was combined with antiandrogens and taxanes, indicating the potential for this combination in treating resistant prostate cancer. Treatment with LX1 significantly decreased tumor volume, serum PSA levels, as well as reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 was found to overcome resistance to enzalutamide treatment, and its combination with enzalutamide further suppressed tumor growth in both the CWR22Rv1 xenograft and LuCaP35CR PDX models. Collectively, the dual effect of LX1 in reducing AR signaling and intratumoral testosterone, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer.
2024-07-18 | GSE271696 | GEO
Project description:Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival (OS) from endocrine therapies in castration resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 biology and expression in prostate cancer (PC) tissue. Following generation and validation of a novel AR-V7 antibody for immunohistochemistry (IHC); nuclear AR-V7 protein expression was determined for 358 primary prostate samples (358 patients) and 293 metastatic biopsies (194 patients). Associations with disease progression, nuclear AR full length (AR-FL) expression, response to abiraterone and/or enzalutamide, and gene signatures (from three independent cohorts) was determined.
2018-10-19 | GSE118435 | GEO
Project description:Since its discovery, there has been one central issue of significant clinical relevance related to expression of the truncated androgen receptor splice variant-7 (AR-v7), which lacks the C-terminal ligand binding domain and thus acquires ligand-independent transcriptional activity in castration-resistant prostate cancer (CRPC). That question is whether AR-v7 is simply a marker of enhanced AR transcriptional activity characteristic of resistance to 2nd generation androgen receptor signaling inhibitors (ARSi) like Abiraterone and Enzalutamide, or whether it drives lethal resistance to ARSi. To address this question, the present study utilized 4 independently derived CRPC patient-derived xenografts in which the genetic and phenotypic changes could be followed before and after the development of ARSi resistance. This allowed evaluation of the correlation between acquired resistance to ARSi and changes in the expression levels of full length AR (AR-FL) vs. AR-v7 during this process. The combined results document that elevated expression of AR-FL alone is sufficient for Abiraterone- but not Enzalutamide-resistance. This is true even if AR-FL has a gain-of-function mutation. Furthermore, Enzalutamide-resistance is consistently correlated with the acquisition of AR-v7 expression. To directly test the requirement for AR-v7 expression in ARSi-refractory CRPC, CRISPR-Cas9 knockout of AR-FL and/or AR-v7 in LNCaP-95 cells was performed to evaluate in vitro and in vivo growth responses. These results document that AR-v7 drives Enzalutamide-resistance and focuses the critical need to develop therapeutic options to prevent and/or inhibit AR-v7 driven lethal progression of CRPC.
2020-10-11 | GSE149433 | 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.
2014-09-03 | GSE56701 | GEO
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
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
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 performed ATAC-seq using LNCaP model with inducible overexpression of AR-V7 to examine the function of AR-V7. We demonstrated that AR-V7 has “pioneer factor-like” activities to access the androgen-responsive elements (AREs) located at compact chromatin regions. More importantly, we found that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7, and its protein expression was dramatically upregulated at AR-V7-induced bone lesions.
2024-06-05 | GSE221137 | GEO
Project description:This study aimed at exploring how would the novel AR N-terminal inhibitor affect the androgen receptor (AR) transcriptome, especially a subset of genes that are uniquely upregulated by AR-V7 in castration resistant prostate cancer cells. We performed next-generation sequencing-based gene expression profiling (RNA-sequencing) on the castration-resistant prostate cancer celll line LNCaP-95. LNCaP-95 expresses high level of endogeneous AR-V7, and also acquired an adaptive shift towards AR-V7-mediated AR signaling activity. Beside regulating the transcription of a subset of canonical wildtype AR genes, AR-V7 also mediates a distinct transcriptional program that is independent of wildtype AR in LNCaP-95. In this experiment, LNCaP-95 cells were treated with vehicle control or the AR-N terminal inhibitor SC912. The subsequent AR transcriptomic change following compound treatment, especially the AR-V7 unique genes were assessed by RNA-seq.
2024-04-30 | GSE253122 | GEO