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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244716 | GEO | 2023/10/10

REPOSITORIES: GEO

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

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2014-04-25 | E-GEOD-55063 | biostudies-arrayexpress

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