Rewiring the transcriptome of castration-resistant prostate cancer through CDK9 inhibition dataset 3
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB62517 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR11471918.fastq.gz | Fastqsanger.gz | |||
| ERR11471919.fastq.gz | Fastqsanger.gz | |||
| ERR11471920.fastq.gz | Fastqsanger.gz | |||
| ERR11471921.fastq.gz | Fastqsanger.gz | |||
| ERR11471922.fastq.gz | Fastqsanger.gz |
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Project description:The rewiring of transcriptional and epigenetic programs is a hallmark of cancer and a targetable vulnerability for treating metastatic cancers. CDK9, whose primary function is to promote transcriptional elongation at active gene promoters, is emerging as a therapeutic target with broad efficacy in various cancer types. We used the novel and selective CDK9 inhibitor PRT2527 to demonstrate this approach's therapeutic efficacy and tolerability in multiple preclinical tumor models with specific transcriptional dependencies. In castration-resistant prostate cancer (CRPC), PRT2527 inhibited CDK9, AR and other transcription factors (e.g., c-MYC, STAT3, and NF-kB) implicated in disease progression and treatment resistance. PRT2527 reduced the proliferation of tumor cell lines and the growth of 3D tumor organoids and spheroids, demonstrating the impact on the bulk tumor cells and the stem-like subpopulation in human and murine CRPC models. PRT2527 was also highly active in vivo in patient-derived CRPC models LuCaP 35 and LuCap 145.2) and transgenic Pb-Cre4;Ptenflox/flox;R26ERG (ERG/PTEN) mice. Notably, PRT2527 induced relevant changes in gene expression, reflecting the impact on the distinct transcriptional programs of various CRPC models. Despite this heterogeneity, a common core of genes and pathways related to oncogenesis was affected in all models. Our data further demonstrate the efficacy and safety of CDK9 inhibition in multiple models of transcriptionally addicted solid tumors. Given its role in transcription, CDK9 is an ideal target for developing novel therapeutic strategies to block tumor cell plasticity driving tumor progression, metastatic spread, and treatment resistance.
2026-06-04 | E-MTAB-12991 | biostudies-arrayexpress
Project description:The rewiring of transcriptional and epigenetic programs is a hallmark of cancer and a targetable vulnerability for treating metastatic cancers. CDK9, whose primary function is to promote transcriptional elongation at active gene promoters, is emerging as a therapeutic target with broad efficacy in various cancer types. We used the novel and selective CDK9 inhibitor PRT2527 to demonstrate this approach's therapeutic efficacy and tolerability in multiple preclinical tumor models with specific transcriptional dependencies. In castration-resistant prostate cancer (CRPC), PRT2527 inhibited CDK9, AR and other transcription factors (e.g., c-MYC, STAT3, and NF-B) implicated in disease progression and treatment resistance. PRT2527 reduced the proliferation of tumor cell lines and the growth of 3D tumor organoids and spheroids, demonstrating the impact on the bulk tumor cells and the stem-like subpopulation in human and murine CRPC models. PRT2527 was also highly active in vivo in patient-derived CRPC models LuCaP 35 and LuCap 145.2) and transgenic Pb-Cre4;Ptenflox/flox;R26ERG (ERG/PTEN) mice. Notably, PRT2527 induced relevant changes in gene expression, reflecting the impact on the distinct transcriptional programs of various CRPC models. Despite this heterogeneity, a common core of genes and pathways related to oncogenesis was affected in all models. Our data further demonstrate the efficacy and safety of CDK9 inhibition in multiple models of transcriptionally addicted solid tumors. Given its role in transcription, CDK9 is an ideal target for developing novel therapeutic strategies to block tumor cell plasticity driving tumor progression, metastatic spread, and treatment resistance.
2026-06-04 | E-MTAB-12987 | biostudies-arrayexpress
Project description:The rewiring of transcriptional and epigenetic programs is a hallmark of cancer and a targetable vulnerability for treating metastatic cancers. CDK9, whose primary function is to promote transcriptional elongation at active gene promoters, is emerging as a therapeutic target with broad efficacy in various cancer types. We used the novel and selective CDK9 inhibitor PRT2527 to demonstrate this approach's therapeutic efficacy and tolerability in multiple preclinical tumor models with specific transcriptional dependencies. In castration-resistant prostate cancer (CRPC), PRT2527 inhibited CDK9, AR and other transcription factors (e.g., c-MYC, STAT3, and NF-B) implicated in disease progression and treatment resistance. PRT2527 reduced the proliferation of tumor cell lines and the growth of 3D tumor organoids and spheroids, demonstrating the impact on the bulk tumor cells and the stem-like subpopulation in human and murine CRPC models. PRT2527 was also highly active in vivo in patient-derived CRPC models LuCaP 35 and LuCap 145.2) and transgenic Pb-Cre4;Ptenflox/flox;R26ERG (ERG/PTEN) mice. Notably, PRT2527 induced relevant changes in gene expression, reflecting the impact on the distinct transcriptional programs of various CRPC models. Despite this heterogeneity, a common core of genes and pathways related to oncogenesis was affected in all models. Our data further demonstrate the efficacy and safety of CDK9 inhibition in multiple models of transcriptionally addicted solid tumors. Given its role in transcription, CDK9 is an ideal target for developing novel therapeutic strategies to block tumor cell plasticity driving tumor progression, metastatic spread, and treatment resistance.
2026-04-08 | E-MTAB-12986 | biostudies-arrayexpress
Project description:ATAC-seq to investigate rewiring the transcriptome of castration-resistant prostate cancer through CDK9 inhibition dataset 1
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Project description:RNA-seq to investigate rewiring the transcriptome of castration-resistant prostate cancer through CDK9 inhibition dataset 2
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Project description:Androgen receptor (AR) signaling is a primary oncogenic driver of castration-resistant prostate cancer (CRPC), yet the mechanism remains incompletely understood. Dysregulation of the AR co-regulatory network has emerged as a key driver of castration resistance. To identify AR-interacting proteins linked to CRPC progression, we performed proteomics-based rapid immunoprecipitation of endogenous proteins (RIME) analysis targeting AR in the CRPC cell line C4-2B.
2026-06-08 | PXD067138 | Pride
Project description:The integration of diverse ‘omic’ datasets will increase our understanding of the key signaling pathways that drive disease. Here, we used clinical tissue cohorts corresponding to lethal metastatic castration resistant prostate cancer (CRPC) obtained at rapid autopsy to integrate mutational, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed transcriptional master regulators, functionally mutated genes, and differentially ‘activated’ kinases in CRPC tissues to synthesize a robust signaling network consisting of pathways with known and novel gene interactions. For 6 individual CRPC patients for which we had transcriptomic and phosphoproteomic data we observed distinct pathway activation states for each patient profile. In one patient, the activated pathways were strikingly similar to a prostate cancer cell line, 22Rv1, providing us with a good pre-clinical model to test targeted, combination therapies. In all, synthesis of multiple ‘omic’ datasets revealed a plethora of pathway information suitable for targeted therapies in lethal prostate cancer.
2016-08-19 | PXD002286 | Pride
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: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:BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration resistant prostate cancer (CRPC) cells. Bromodomain and extraterminal protein (BET) inhibitors displace BRD4 protein from chromatin, resulting in the inhibition of oncogenic transcriptional programs. Several BET inhibitors (BETi) are currently being evaluated in clinical trials for a variety of malignancies, including CRPC. Here we describe a general mechanism of acquired resistance to BETi due to modulation of cellular pathways that are amenable to targeted therapies in CRPC cells. BETi resistant CRPC cells displayed cross resistance to a variety of BETi in the absence of gatekeeper mutations or persistent drug pump activation. Resistant cells exhibited reduced chromatin bound BRD4, and were less sensitive to Proteolysis Targeting Chimeric (PROTAC) -mediated degradation or genetic knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR-signaling due to CDK9-mediated serine-81 phosphorylation of AR, with a consequent increase in sensitivity to CDK9 inhibitors and enzalutamide in BETi resistant cells. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DNA damage response (DDR) genes was observed due to the loss of BRD4 from their proximal promoter regions in the resistant cells, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy in CRPC. However, data showing the reactivation of AR-signaling and increased DNA damage in the BETi resistant cells provide unique opportunities for combination therapies in managing CRPC.
2018-02-27 | GSE103082 | GEO