Similar Datasets
Project description:Acquisition of resistance to the next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castrate-resistant prostate cancer (CRPC). Most ENZ-resistant (ENZ-R) CRPCs are androgen receptor (AR)-positive (CRPCAR+), but often negative for prostate-specific antigen (PSA), a well-established surrogate of AR activity, implying the emergence of AR-indifferent disease. Through genome-wide ChIP-seq and RNA-seq profiling in disease-relevant ENZ-R CRPCAR+ cells, we identified a unique set of gained AR binding sites (ARBS-G) lacking the canonical DNA binding elements of AR and the pioneer factor FOXA1. ARBS-G loci are highly enriched with CpG islands and significantly overlapped with the binding sites of the unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. Expression of CXXC5 and its downstream targets including inhibitor of differentiation-1 (ID1) was upregulated in ENZ-R CRPCAR+ cell lines, patient-derived xenografts (PDXs) and patient specimens. Genetic depletion of AR, CXXC5 or ID1 restored ENZ sensitivity in human ENZ-R CRPCAR+ cells. Most importantly, ENZ-R CRPCAR+ cells, organoids, xenografts and PDXs were invariably hypersensitive to the novel BET-CBP/p300 dual inhibitor NEO2734. These results reveal that ENZ-R CRPCAR+ cancers are only indifferent to the canonical AR (cAR) activity, but remain addictive to the noncanonical AR (ncAR) function which is selectively vulnerable upon dual inhibition of CBP/p300 and BET family proteins.
2020-08-20 | GSE136129 | GEO
Project description:Acquisition of resistance to the next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castrate-resistant prostate cancer (CRPC). Most ENZ-resistant (ENZ-R) CRPCs are androgen receptor (AR)-positive (CRPCAR+), but often negative for prostate-specific antigen (PSA), a well-established surrogate of AR activity, implying the emergence of AR-indifferent disease. Through genome-wide ChIP-seq and RNA-seq profiling in disease-relevant ENZ-R CRPCAR+ cells, we identified a unique set of gained AR binding sites (ARBS-G) lacking the canonical DNA binding elements of AR and the pioneer factor FOXA1. ARBS-G loci are highly enriched with CpG islands and significantly overlapped with the binding sites of the unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. Expression of CXXC5 and its downstream targets including inhibitor of differentiation-1 (ID1) was upregulated in ENZ-R CRPCAR+ cell lines, patient-derived xenografts (PDXs) and patient specimens. Genetic depletion of AR, CXXC5 or ID1 restored ENZ sensitivity in human ENZ-R CRPCAR+ cells. Most importantly, ENZ-R CRPCAR+ cells, organoids, xenografts and PDXs were invariably hypersensitive to the novel BET-CBP/p300 dual inhibitor NEO2734. These results reveal that ENZ-R CRPCAR+ cancers are only indifferent to the canonical AR (cAR) activity, but remain addictive to the noncanonical AR (ncAR) function which is selectively vulnerable upon dual inhibition of CBP/p300 and BET family proteins.
2020-08-20 | GSE136128 | GEO
Project description:Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.
| S-EPMC7943793 | biostudies-literature
Project description:An unorthodox AR addiction drives enzalutamide resistance in prostate cancer
| PRJNA561348 | ENA
Project description:An unorthodox AR addiction drives enzalutamide resistance in prostate cancer (ChIP-Seq)
| PRJNA561351 | ENA
Project description:An unorthodox AR addiction drives enzalutamide resistance in prostate cancer (RNA-Seq)
| PRJNA561352 | ENA
Project description:The refractory of castration-resistant prostate cancer (CRPC) is mainly reflected in drug resistance. The current research on the resistance mechanism of CRPC is still in its infancy. In this study, we revealed for the first time the key role of LncRNA PCBP1-AS1 in CRPC drug resistance. Through detailed in vivo and in vitro studies, we found that PCBP1-AS1 may enhance the deubiquitination of AR/AR-V7 by stabilizing the USP22-AR/AR-V7 complex, thereby preventing AR/AR-V7 from being degraded through the ubiquitin-proteasome pathway. Targeting PCBP1-AS1 can significantly restore the drug sensitivity of enzalutamide-resistant tumors in vivo and in vitro. Our research further expands the function of LncRNA in castration-resistant prostate cancer, which may provide new potential for clinical diagnosis and targeted therapy.
| S-EPMC8452729 | biostudies-literature
Project description:The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone.We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival.A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA.Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).
| S-EPMC4201502 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-05-20 | GSE150896 | GEO
Project description:Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment.
| S-EPMC8004828 | biostudies-literature