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Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 InhibitorsModulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156885 | GEO | 2020/10/05

REPOSITORIES: GEO

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Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [SLAM-seq]

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.

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Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 InhibitorsModulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

Project description:Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 InhibitorsModulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

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Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ChIP-seq]

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Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ATAC-seq]

Project description:Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ATAC-seq]

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Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [SLAM-seq]

Project description:Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [SLAM-seq]

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Project description:The androgen receptor (AR) is important for prostate cancer development and progression. Genome-wide mapping of AR binding sites in prostate cancer has found that the majority of AR binding sites are located within non-promoter regions. These distal AR binding regions regulate AR target genes (e.g. UBE2C) involved in prostate cancer growth through chromatin looping. In addition to long-distance gene regulation, looping has been shown to induce spatial proximity of two genes otherwise located far away along the genomic sequence and the formation of double-strand DNA breaks, resulting in aberrant gene fusions (e.g. TMPRSS2-ERG) that also contribute to prostate tumorigenesis. Elucidating the mechanisms of AR-driven chromatin looping will increase our understanding of prostate carcinogenesis and may lead to the identification of new therapeutic targets.

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