Recent studies indicate that replication checkpoint modulators (RCMs) such as inhibitors of CHK1, ATR, and WEE1 have promising monotherapy activity in solid tumors, including platinum-resistant high grade serous ovarian cancer (HGSOC). However, clinical response rates are generally below 30%. While RCM-induced DNA damage has been extensively examined in preclinical and clinical studies, the link between replication checkpoint interruption and tumor shrinkage remains incompletely understood. Here we utilized HGSOC cell lines and patient-derived xenografts (PDXs) to study events leading from RCM treatment to ovarian cancer cell death. These studies show that RCMs increase CDC25A levels and CDK2 signaling in vitro, leading to dysregulated cell cycle progression and increased replication stress in HGSOC cell lines independent of homologous recombination status. These events lead to sequential activation of JNK and multiple BH3-only proteins, including BCL2L11/BIM, BBC3/PUMA and the BMF, all of which are required to fully initiate RCM-induced apoptosis. Activation of the same signaling pathway occurs in HGSOC PDXs that are resistant to poly(ADP-ribose) polymerase inhibitors but respond to RCMs ex vivo with a decrease in cell number in 3-dimensional culture and in vivo with xenograft shrinkage or a significantly diminished growth rate. These findings identify key cell death-initiating events that link replication checkpoint inhibition to antitumor response in ovarian cancer.

中文翻译：

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JNK 敏感的仅 BH3 蛋白的促凋亡活性是卵巢癌对复制检查点抑制剂反应的基础


最近的研究表明，CHK1、ATR 和 WEE1 抑制剂等复制检查点调节剂 （RCM） 在实体瘤中具有很有希望的单药治疗活性，包括铂耐药高级别浆液性卵巢癌 （HGSOC）。然而，临床反应率通常低于 30%。虽然 RCM 诱导的 DNA 损伤已在临床前和临床研究中得到广泛检查，但复制检查点中断与肿瘤缩小之间的联系仍不完全清楚。在这里，我们利用 HGSOC 细胞系和患者来源的异种移植物 （PDX） 来研究从 RCM 治疗到卵巢癌细胞死亡的事件。这些研究表明，RCM 在体外增加 CDC25A 水平和 CDK2 信号传导，导致 HGSOC 细胞系的细胞周期进程失调和复制应激增加，与同源重组状态无关。这些事件导致 JNK 和多种仅含 BH3 的蛋白（包括 BCL2L11/BIM、BBC3/PUMA 和 BMF）的顺序激活，所有这些都是完全启动 RCM 诱导的细胞凋亡所必需的。相同的信号通路激活发生在对聚（ADP-核糖）聚合酶抑制剂耐药的 HGSOC PDX 中，但对离体 RCM 的反应是 3 维培养和体内细胞数量的减少，异种移植物收缩或生长速率显着降低。这些发现确定了将复制检查点抑制与卵巢癌抗肿瘤反应联系起来的关键细胞死亡起始事件。