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

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. Overall design: RNA-seq analysis of LNCaP cells following 4 hours of CDKI-73 treatment (250nM) or DMSO control.

细胞周期蛋白依赖性激酶9（Cyclin-dependent kinase 9, CDK9）可激活癌症中的致癌转录通路。本研究评估了一种口服生物可利用的CDK9抑制剂CDKI-73在前列腺癌中的活性，前列腺癌是一类以多种转录调控因子异常活化为特征的疾病。CDKI-73可在多种体外模型中抑制细胞增殖并诱导细胞死亡，这些模型涵盖了雄激素受体（androgen receptor, AR）依赖性及非依赖性的去势抵抗性前列腺癌（castration-resistant prostate cancer, CRPC）模型。该抑制剂的活性在更具临床相关性的体系中得到验证，包括异种移植瘤、患者来源肿瘤外植体以及侵袭性患者来源CRPC类器官。机制层面，CDKI-73可抑制CDK9介导的RNA聚合酶II丝氨酸2位点及AR丝氨酸81位点的磷酸化。这一效应可降低抗凋亡因子的表达水平，并抑制AR、MYC及BRD4所调控的信号通路——上述因子均为前列腺癌中转录失调的关键驱动因素。CDKI-73与BRD4抑制剂AZD5153在侵袭性AR依赖性及非依赖性疾病的细胞系与类器官模型中展现出协同抗肿瘤活性。综上，本研究为CDK9的致癌活性提供了新的见解，并揭示CDKI-73是一种极具潜力的前列腺癌治疗药物，尤其针对侵袭性、治疗抵抗性的前列腺癌亚型。实验整体设计：对经250nM CDKI-73处理4小时的LNCaP细胞进行RNA测序（RNA-seq）分析，以二甲基亚砜（DMSO）作为空白对照。