Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Cancer Treat Res. 2023;186:285-298. doi: 10.1007/978-3-031-30065-3_15.
Polymerase theta (POLθ) is the critical multi-domain enzyme in microhomology-mediated end-joining DNA double-stranded break repair. POLθ is expressed at low levels in normal tissue but is often overexpressed in cancers, especially in DNA repair deficient cancers, such as homologous-recombination cancers, rendering them exquisitely sensitive to POLθ inhibition secondary to synthetic lethality. Development of POLθ inhibitors is an active area of investigation with inhibitors of the N-terminal helicase domain or the C-terminal polymerase domain currently in clinical trial. Here, we review POLθ-mediated microhomology-mediated end-joining, the development of POLθ inhibitors, and the potential clinical uses of POLθ inhibitors.
聚合酶θ（POLθ）是微同源介导的末端连接 DNA 双链断裂修复中关键的多结构域酶。POLθ 在正常组织中的表达水平较低，但在癌症中经常过表达，尤其是在 DNA 修复缺陷的癌症中，如同源重组癌症，这使得它们对 POLθ 抑制极为敏感，从而导致合成致死。POLθ 抑制剂的开发是一个活跃的研究领域，目前有针对 N 端解旋酶结构域或 C 端聚合酶结构域的抑制剂正在临床试验中。在这里，我们综述了 POLθ 介导的微同源介导的末端连接、POLθ 抑制剂的开发以及 POLθ 抑制剂的潜在临床用途。
