RNA-seq to investigate rewiring the transcriptome of castration-resistant prostate cancer through CDK9 inhibition dataset 2
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB62516 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR11471818.fastq.gz | Fastqsanger.gz | |||
| ERR11471819.fastq.gz | Fastqsanger.gz | |||
| ERR11471820.fastq.gz | Fastqsanger.gz | |||
| ERR11471821.fastq.gz | Fastqsanger.gz | |||
| ERR11471822.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-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.
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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:ATAC-seq to investigate rewiring the transcriptome of castration-resistant prostate cancer through CDK9 inhibition dataset 1
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Project description:Rewiring the transcriptome of castration-resistant prostate cancer through CDK9 inhibition dataset 3
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Project description:CDK9 is the kinase subunit of P-TEFb that enables RNA polymerase (Pol) II to transit from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to the lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9’s activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb’s loss of activity, only the simultaneous inhibition of CDK9 and MYC can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy. We used microarrays to examine the global impact on gene expression by imhibiting CDK9 at different time durations. HeLa cell lines treated with CDK9 inhibitor at different time points
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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.
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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:CDK9 is the kinase subunit of P-TEFb that enables RNA polymerase (Pol) II to transit from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to the lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9’s activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb’s loss of activity, only the simultaneous inhibition of CDK9 and MYC can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy. ChIP-seq of Pol II in HeLa cells before or after i-CDk9 treatment
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