We analyzed the efficacy and mechanistic interactions of PARP inhibition (PARPi; olaparib) and CDK4/6 inhibition (CDK4/6i; palbociclib or abemaciclib) combination therapy in castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) models. We demonstrated that combined olaparib and palbociblib or abemaciclib treatment resulted in synergistic suppression of the p-Rb1–E2F1 signaling axis at the transcriptional and posttranslational levels, leading to disruption of cell-cycle progression and inhibition of E2F1 gene targets, including genes involved in DDR signaling/damage repair, antiapoptotic BCL-2 family members ( BCL-2 and MCL-1 ), CDK1 , and neuroendocrine differentiation (NED) markers in vitro and in vivo . In addition, olaparib + palbociclib or olaparib + abemaciclib combination treatment resulted in significantly greater growth inhibition and apoptosis than either single agent alone. We further showed that PARPi and CDK4/6i combination treatment–induced CDK1 inhibition suppressed p-S70-BCL-2 and increased caspase cleavage, while CDK1 overexpression effectively prevented the downregulation of p-S70-BCL-2 and largely rescued the combination treatment–induced cytotoxicity. Our study defines a novel combination treatment strategy for CRPC and NEPC and demonstrates that combination PARPi and CDK4/6i synergistically promotes suppression of the p-Rb1-E2F1 axis and E2F1 target genes, including CDK1 and NED proteins, leading to growth inhibition and increased apoptosis in vitro and in vivo . Taken together, our results provide a molecular rationale for PARPi and CDK4/6i combination therapy and reveal mechanism-based clinical trial opportunities for men with NEPC.

中文翻译：

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PARP 和 CDK4/6 抑制剂联合治疗在前列腺癌中诱导细胞凋亡并抑制神经内分泌分化

我们分析了 PARP 抑制（PARPi；olaparib）和 CDK4/6 抑制（CDK4/6i；palbociclib 或 abemaciclib）联合治疗在去势抵抗性前列腺癌 (CRPC) 和神经内分泌前列腺癌 (NEPC) 模型中的疗效和机制相互作用。我们证明了 olaparib 和 palbociblib 或 abemaciclib 联合治疗导致 p-Rb1-E2F1 信号轴在转录和翻译后水平的协同抑制，导致细胞周期进程的中断和 E2F1 基因靶点的抑制，包括参与 DDR 的基因信号/损伤修复、抗凋亡 BCL-2 家族成员（BCL-2 和 MCL-1）、CDK1 和体外和体内神经内分泌分化 (NED) 标志物。此外，olaparib + palbociclib 或 olaparib + abemaciclib 联合治疗导致生长抑制和细胞凋亡显着高于单独使用任何一种药物。我们进一步表明，PARPi 和 CDK4/6i 联合治疗诱导的 CDK1 抑制抑制了 p-S70-BCL-2 并增加了 caspase 裂解，而 CDK1 过表达有效地阻止了 p-S70-BCL-2 的下调，并在很大程度上挽救了联合治疗——诱导的细胞毒性。我们的研究为 CRPC 和 NEPC 定义了一种新的联合治疗策略，并证明 PARPi 和 CDK4/6i 的组合协同促进 p-Rb1-E2F1 轴和 E2F1 靶基因（包括 CDK1 和 NED 蛋白）的抑制，从而导致生长抑制和细胞凋亡增加体外和体内。综合起来，