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Multifaceted anti-tumor activity of a CDK9 inhibitor in prostate cancer [RNA-seq]

ABSTRACT: Multifaceted anti-tumor activity of a CDK9 inhibitor in prostate cancer [RNA-seq]

PROVIDER: PRJNA1024438 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26297661.fastq.gz	Fastqsanger.gz
	SRR26297662.fastq.gz	Fastqsanger.gz
	SRR26297663.fastq.gz	Fastqsanger.gz
	SRR26297664.fastq.gz	Fastqsanger.gz
	SRR26297665.fastq.gz	Fastqsanger.gz

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Multifaceted anti-tumor activity of a CDK9 inhibitor in prostate cancer

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Multifaceted anti-tumor activity of a CDK9 inhibitor in prostate cancer [ChIP-seq]

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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Multifaceted anti-tumor activity of a CDK9 inhibitor in prostate cancer [RNA-seq]

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Multifaceted anti-tumor activity of a CDK9 inhibitor in prostate cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-02-07 | GSE255309 | GEO

Expression profiling of HeLa cell line treated with CDK9 inhibitor

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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Inhibition of CDK9 activity compromises global splicing in prostate cancer cells

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.

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Project description:non-Hodgkins lymphoma cells were treated with a CDK9 inhibitor to determine which proteins and phosphorylation events are affected by CDK9 in lymphoma.

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Project description:we reported a novel CDK9 high selective inhibitor JSH-009, it displayed high potency against CDK9 (IC50=1nM) and achieved high selectivity over CDKs family kinases (range from 200-10000 fold). JSH-009 showed high potent anti-proliferation effect in a range of AML cells and primary patient cells through downregulation of a number of transcriptional, apoptotic genes and related signaling pathways. In addition, this compound exhibited great anti-leukemic efficacy in the MV4-11 mediated xenograft, engraftment and AML PDX preclinical models. Currently, JSH-009 is under extensive preclinical development and We believe the work presented here would be of great interest to readers of Leukemia.

2019-02-28 | GSE123287 | GEO

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Project description:Cyclin-Dependent Kinase 9 (CDK9) as part of the PTEFb complex promotes transcriptional elongation by promoting RNAPII pause release. We now report that, paradoxically, CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell screen, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression and cell differentiation, along with activation of endogenous retrovirus (ERV) genes. CDK9 inhibition dephosphorylates the SWI/SNF protein SMARCA4 and represses HP1α expression, both of which contribute to gene reactivation. Based on gene activation, we developed the highly selective and potent CDK9 inhibitor MC180295 (IC50 =5.1nM) that has broad anti-cancer activity in-vitro and is effective in in-vivo cancer models. Additionally, CDK9 inhibition sensitizes with the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.

2020-05-26 | PXD007925 | Pride

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