Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE156882 | GEO | 2020/10/05
REPOSITORIES: GEO
Similar Datasets
Project description:Castration resistant prostate cancers (CRPCs) lose sensitivity to androgen deprivation therapies but frequently remain dependent on oncogenic transcription driven by androgen receptor (AR) and its splice variants. To discover novel modulators of AR variant activity, we used a lysate-based small molecule microarray (SMM) assay and identified KI-ARv-03 as an AR variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742 , an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo , oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.
2020-10-05 | GSE156884 | GEO
Project description:Castration resistant prostate cancers (CRPCs) lose sensitivity to androgen deprivation therapies but frequently remain dependent on oncogenic transcription driven by androgen receptor (AR) and its splice variants. To discover novel modulators of AR variant activity, we used a lysate-based small molecule microarray (SMM) assay and identified KI-ARv-03 as an AR variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742 , an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo , oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.
2020-10-05 | GSE156881 | GEO
Project description:Androgen receptor (AR) splice variants (ARVs) are implicated in developing castration-resistant (CR) prostate cancer (CRPC). Little is known about the ARV-mediated transcription program in CRPC. We identified ARV-preferred binding sites (ARV-PBS) and unique transcriptome in CRPC cells. ARVs preferentially bind to enhancers located in nucleosome-depleted regions with the full AR-response element (AREfull), while full-length AR (ARFL)-PBS are enhancers resided in closed chromatin regions with the composite FOXA1-nnnn-AREhalf motif. ARV-PBS exclusively overlapped with AR binding sites in CR patients. ARV-driven genes were up-regulated in abiraterone-resistant patient specimens and promote CRPC growth. We uncover distinct genomic and epigenomic characteristics of ARV-PBS and a unique ARV-dependent transcriptional program that not only drives CR progression but could also offer new targets for therapy. Increasing evidence suggests a pivotal role of ARVs in the acquisition of anti-AR therapy resistance in CRPC. It has been shown previously that ARVs possess unique structural and functional features such as completely lacking or only containing an impaired ligand-binding domain but constitutively active. Our findings advance the understanding of ARVs by demonstrating that ARV-PBS exhibit distinctive DNA-binding motif, GC content, and nucleosome and epigenetic characteristics. We further unravel that ARV-PBS exclusively overlap with AR bindings identified from castration-resistant patients and ARV activity is significantly increased in abiraterone-resistant patients. Given that there is no drug available to target ARVs at present, identification of ARV-mediated unique downstream pathways opens new avenues for the development of effective therapeutics for CRPC.
2018-03-07 | GSE80742 | GEO
Project description:Androgen receptor (AR) splice variants (ARVs) are implicated in developing castration-resistant (CR) prostate cancer (CRPC). Little is known about the ARV-mediated transcription program in CRPC. We identified ARV-preferred binding sites (ARV-PBS) and unique transcriptome in CRPC cells. ARVs preferentially bind to enhancers located in nucleosome-depleted regions with the full AR-response element (AREfull), while full-length AR (ARFL)-PBS are enhancers resided in closed chromatin regions with the composite FOXA1-nnnn-AREhalf motif. ARV-PBS exclusively overlapped with AR binding sites in CR patients. ARV-driven genes were up-regulated in abiraterone-resistant patient specimens and promote CRPC growth. We uncover distinct genomic and epigenomic characteristics of ARV-PBS and a unique ARV-dependent transcriptional program that not only drives CR progression but could also offer new targets for therapy. Increasing evidence suggests a pivotal role of ARVs in the acquisition of anti-AR therapy resistance in CRPC. It has been shown previously that ARVs possess unique structural and functional features such as completely lacking or only containing an impaired ligand-binding domain but constitutively active. Our findings advance the understanding of ARVs by demonstrating that ARV-PBS exhibit distinctive DNA-binding motif, GC content, and nucleosome and epigenetic characteristics. We further unravel that ARV-PBS exclusively overlap with AR bindings identified from castration-resistant patients and ARV activity is significantly increased in abiraterone-resistant patients. Given that there is no drug available to target ARVs at present, identification of ARV-mediated unique downstream pathways opens new avenues for the development of effective therapeutics for CRPC.
2018-03-07 | GSE80741 | GEO
Project description:Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer. Here, we evaluate the activity of an orally bioavailable CDK9 inhibitor, CDKI-73, in prostate cancer, a disease characterized by aberrant activity of multiple transcriptional regulators. CDKI-73 caused inhibition of proliferation and cell death in diverse in vitro models of androgen receptor (AR)-driven and AR-independent models of castration-resistant prostate cancer (CRPC). The activity of CDKI-73 was validated in more clinically-relevant systems, including xenografts, patient-derived tumor explants and aggressive patient-derived CRPC organoids. Mechanistically, CDKI-73 inhibited CDK9-mediated phosphorylation of serine 2 on RNA polymerase II and serine 81 on AR. This resulted in reduced levels of anti-apoptotic factors and suppression of signaling pathways regulated by AR, MYC and BRD4, key drivers of dysregulated transcription in prostate cancer. CDKI-73 synergized with the BRD4 inhibitor AZD5153 in cell lines and organoid models of aggressive AR-driven and AR-independent disease. Collectively, our work provides new insights into CDK9’s oncogenic activity and reveals CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.
2024-02-25 | GSE255308 | GEO
Project description:Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer. Here, we evaluate the activity of an orally bioavailable CDK9 inhibitor, CDKI-73, in prostate cancer, a disease characterized by aberrant activity of multiple transcriptional regulators. CDKI-73 caused inhibition of proliferation and cell death in diverse in vitro models of androgen receptor (AR)-driven and AR-independent models of castration-resistant prostate cancer (CRPC). The activity of CDKI-73 was validated in more clinically-relevant systems, including xenografts, patient-derived tumor explants and aggressive patient-derived CRPC organoids. Mechanistically, CDKI-73 inhibited CDK9-mediated phosphorylation of serine 2 on RNA polymerase II and serine 81 on AR. This resulted in reduced levels of anti-apoptotic factors and suppression of signaling pathways regulated by AR, MYC and BRD4, key drivers of dysregulated transcription in prostate cancer. CDKI-73 synergized with the BRD4 inhibitor AZD5153 in cell lines and organoid models of aggressive AR-driven and AR-independent disease. Collectively, our work provides new insights into CDK9’s oncogenic activity and reveals CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.
2023-10-10 | GSE244716 | GEO
Project description:The mainstay treatment for men with metastatic prostate cancer is androgen deprivation therapy (ADT), which inhibits androgen biosynthesis and/or binding of ligand to the androgen receptor (AR). Most men respond to ADT, but all subsequently develop resistance and progression to incurable and lethal castration-resistant prostate cancer (CRPC). CRPC generally remains driven by the AR: therefore, the development of novel AR-targeted therapies, as well as elucidating therapy-driven changes to the AR signalling axis that mediate resistance, remain priorities for the field. Using a novel and powerful proteomic technique, rapid immunoprecipitation of endogenous proteins (RIME), we have identified a new AR binding protein, the transcription factor Grainyhead-like 2 (GRHL2), and shown that it plays an essential, multifaceted role in signalling by the canonical AR and by constitutively active truncated AR variants (ARVs). GRHL2 is necessary for the maintenance of AR/ARV expression in multiple prostate cancer model systems, co-localises with AR at specific sites on chromatin to enhance the androgen-regulated transcriptional program, and is required for optimal prostate cancer growth. Interestingly, we found that GRHL2 is itself an AR/ARV-regulated gene, creating a positive feed-forward loop between the two factors. The GRHL2 gene is frequently amplified and upregulated in CRPC, thereby potentially enabling further amplification AR signalling in the drug-resistant setting. In summary, this study has identified a critical new AR coregulator and potential therapeutic target in prostate cancer.
2017-04-01 | GSE80450 | GEO
Project description:The mainstay treatment for men with metastatic prostate cancer is androgen deprivation therapy (ADT), which inhibits androgen biosynthesis and/or binding of ligand to the androgen receptor (AR). Most men respond to ADT, but all subsequently develop resistance and progression to incurable and lethal castration-resistant prostate cancer (CRPC). CRPC generally remains driven by the AR: therefore, the development of novel AR-targeted therapies, as well as elucidating therapy-driven changes to the AR signalling axis that mediate resistance, remain priorities for the field. Using a novel and powerful proteomic technique, rapid immunoprecipitation of endogenous proteins (RIME), we have identified a new AR binding protein, the transcription factor Grainyhead-like 2 (GRHL2), and shown that it plays an essential, multifaceted role in signalling by the canonical AR and by constitutively active truncated AR variants (ARVs). GRHL2 is necessary for the maintenance of AR/ARV expression in multiple prostate cancer model systems, co-localises with AR at specific sites on chromatin to enhance the androgen-regulated transcriptional program, and is required for optimal prostate cancer growth. Interestingly, we found that GRHL2 is itself an AR/ARV-regulated gene, creating a positive feed-forward loop between the two factors. The GRHL2 gene is frequently amplified and upregulated in CRPC, thereby potentially enabling further amplification AR signalling in the drug-resistant setting. In summary, this study has identified a critical new AR coregulator and potential therapeutic target in prostate cancer.
2017-04-01 | GSE80256 | GEO
Project description:Cyclin-dependent kinase 9 (CDK9) phosphorylates RNA polymerase II to promote productive transcription elongation and the phosphorylation also regulates recruitment of the splicing machinery. Here we show that acute CDK9 inhibition affects splicing of thousands of mRNAs. CDK9 inhibition impairs global splicing and there is no evidence for a coordinated response between alternative splicing and the overall transcriptome. Alternative splicing is feature of aggressive prostate cancer (CRPC) and enables generation of an anti-androgen resistant version of a ligand-independent androgen receptor, AR-v7. We show that CDK9 inhibition compromises splicing of the androgen receptor (AR) mRNA due to the faulty utilization of alternative 3’splice site and introduction of premature stop codon. Consequently, this defective splicing results in the loss of AR and AR-v7 expression in models of CRPC. We show that CDK9 expression increases as PC cells develop CRPC-phenotype both in vitro and also in patient samples.
2022-01-10 | GSE169090 | GEO
Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling. Despite the success of recently approved therapies targeting AR signaling, such as abiraterone and second-generation anti-androgens MDV3100 (enzalutamide), durable responses are limited, presumably due to acquired resistance. Recently, JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Examination of ASH2L genome-wide binding in prostate cancer cells after AR stimulation.
2015-03-02 | E-GEOD-60841 | biostudies-arrayexpress