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一种一流的聚合酶抑制剂选择性地靶向同源重组缺陷肿瘤

原文发布日期：2021-06-17

英文摘要：

摘要翻译：

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文章：

一种一流的聚合酶抑制剂选择性地靶向同源重组缺陷肿瘤

A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors

原文发布日期：2021-06-17

英文摘要：

DNA polymerase theta (POLθ or POLQ) is synthetic lethal with homologous recombination (HR) deficiency and is thus a candidate target for HR-deficient cancers. Through high-throughput small-molecule screens, we identified the antibiotic novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo. NVB directly binds to the POLθ ATPase domain, inhibits its ATPase activity and phenocopies POLθ depletion. NVB kills HR-deficient breast and ovarian tumors in genetically engineered mouse models and xenograft and patient-derived xenograft models. Increased POLθ levels predict NVB sensitivity, and HR-deficient tumor cells with acquired resistance to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are sensitive to NVB in vitro and in vivo. Mechanistically, NVB-mediated cell death in PARPi-resistant cells arises from increased double-strand break end resection, leading to accumulation of single-stranded DNA intermediates and nonfunctional foci of the recombinase RAD51. Our results demonstrate that NVB may be useful alone or in combination with PARPi for treating HR-deficient tumors, including those with acquired PARPi resistance.

摘要翻译：

DNA聚合酶θ（POLθ或POLQ）与重组过程缺陷性癌症之间存在合成性致死关系，因此其是HR缺乏型癌症的目标候选。通过高通量小分子筛选法，我们发现抗生素novobiocin（NVB）是一种特定的POLθ抑制剂，在体内外专一地杀死HR缺陷肿瘤细胞。NVB直接结合到POLθATP酶域，抑制其水解活性并模拟POLθ减少的效果。NVB在遗传模型的小鼠和人源化肿瘤模型中杀死HR缺乏的乳腺和卵巢肿瘤。POLθ水平增加预测NVB敏感性，在HR缺乏且获得PARP（聚(核糖核苷酸二酯)聚合酶）抑制剂耐药性肿瘤细胞中，NVB体内外均导致敏感。机制上，NVB通过在PARPi耐药细胞中增加双链断裂末端修复作用导致的单链DNA积累和不功能性重组酶RAD51焦点而产生细胞死亡。我们的结果表明，NVB可能作为单独或联合PARPi用于治疗HR缺陷肿瘤，包括获得性PARPi耐药情况。