Purpose: Despite significant benefit for other cancer subtypes, immune checkpoint blockade (ICB) therapy has not yet been shown to significantly improve outcomes for men with castration-resistant prostate cancer (CRPC). Prior data have shown that DNA damage response (DDR) deficiency, via genetic alteration and/or pharmacologic induction using DDR inhibitors (DDRi), may improve ICB response in solid tumors in part due to induction of mitotic catastrophe and innate immune activation. Discerning the underlying mechanisms of this DDRi–ICB interaction in a prostate cancer–specific manner is vital to guide novel clinical trials and provide durable clinical responses for men with CRPC. Experimental Design: We treated prostate cancer cell lines with potent, specific inhibitors of ATR kinase, as well as with PARP inhibitor, olaparib. We performed analyses of cGAS–STING and DDR signaling in treated cells, and treated a syngeneic androgen-indifferent, prostate cancer model with combined ATR inhibition and anti–programmed death ligand 1 (anti–PD-L1), and performed single-cell RNA sequencing analysis in treated tumors. Results: ATR inhibitor (ATRi; BAY1895433) directly repressed ATR–CHK1 signaling, activated CDK1–SPOP axis, leading to destabilization of PD-L1 protein. These effects of ATRi are distinct from those of olaparib, and resulted in a cGAS–STING-initiated, IFN-β–mediated, autocrine, apoptotic response in CRPC. The combination of ATRi with anti–PD-L1 therapy resulted in robust innate immune activation and a synergistic, T-cell–dependent therapeutic response in our syngeneic mouse model. Conclusions: This work provides a molecular mechanistic rationale for combining ATR-targeted agents with immune checkpoint blockade for patients with CRPC. Multiple early-phase clinical trials of this combination are underway.

中文翻译：

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ATR 抑制诱导 CDK1-SPOP 信号传导并增强前列腺癌中的抗 PD-L1 细胞毒性


目的：尽管免疫检查点阻断（ICB）疗法对其他癌症亚型有显着益处，但尚未被证明可以显着改善去势抵抗性前列腺癌（CRPC）男性的预后。先前的数据表明，DNA 损伤反应 (DDR) 缺陷，通过基因改变和/或使用 DDR 抑制剂 (DDRi) 的药理诱导，可能会改善实体瘤中的 ICB 反应，部分原因是诱导有丝分裂灾难和先天免疫激活。辨别前列腺癌特异性方式中 DDRi-ICB 相互作用的潜在机制对于指导新的临床试验并为患有 CRPC 的男性提供持久的临床反应至关重要。实验设计：我们用强效、特异性的 ATR 激酶抑制剂以及 PARP 抑制剂奥拉帕尼处理前列腺癌细胞系。我们对处理细胞中的 cGAS-STING 和 DDR 信号传导进行了分析，并结合 ATR 抑制和抗程序性死亡配体 1（抗 PD-L1）处理了同基因雄激素无关的前列腺癌模型，并进行了单细胞 RNA 分析。治疗肿瘤的测序分析。结果：ATR抑制剂（ATRi；BAY1895433）直接抑制ATR-CHK1信号传导，激活CDK1-SPOP轴，导致PD-L1蛋白不稳定。 ATRi 的这些作用与奥拉帕尼的作用不同，并导致 CRPC 中 cGAS-STING 启动、IFN-β 介导的自分泌、凋亡反应。 ATRi 与抗 PD-L1 疗法的结合在我们的同基因小鼠模型中产生了强大的先天免疫激活和协同的 T 细胞依赖性治疗反应。结论：这项工作为 CRPC 患者将 ATR 靶向药物与免疫检查点阻断相结合提供了分子机制原理。 该组合的多项早期临床试验正在进行中。