Polymerase θ inhibition steps on the cGAS pedal.
Polymerase θ inhibition steps on the cGAS pedal.
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DOI：
10.1172/jci170660
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发表时间：
2023-06-01
影响因子：
15.9
通讯作者：
Gupta, Gaorav P.
中科院分区：
文献类型：
--
作者：
Smith, Chelsea M.;Gupta, Gaorav P.
同源重组 (HR) 修复缺陷会导致 DNA 损伤累积，并可能使个体易患癌症。聚合酶 theta（Pol θ，由 POLQ 编码）在 HR 缺陷的癌症中过度表达，并通过介导容易出错的双链断裂 (DSB) 修复和促进对聚 ADP 核糖聚合酶抑制剂治疗的耐药性来促进癌细胞存活。在本期 JCI 中，Oh、Wang 等人。关于 Pol θ 抑制对抗肿瘤免疫激活的影响的报告。作者使用了以 HR 相关基因改变和 POLQ 过度表达为特征的胰腺导管腺癌 (PDAC) 细胞和小鼠模型。 POLQ 敲低显示出与涉及 DNA 修复的基因突变（包括 BRCA1、BRCA2 和 ATM）相结合的合成致死性。值得注意的是，Pol θ 缺乏或抑制可抑制肿瘤生长，增加未修复 DNA 损伤的积累，并通过 cGAS/STING 途径增强 T 细胞浸润。这些发现表明，HR 缺陷癌症中 Pol θ 抑制的范围更广。
Deficiencies in homologous recombination (HR) repair lead to an accumulation of DNA damage and can predispose individuals to cancer. Polymerase theta (Pol θ, encoded by POLQ) is overexpressed by HR-deficient cancers and promotes cancer cell survival by mediating error-prone double-stranded break (DSB) repair and facilitating resistance against poly-ADP ribose polymerase inhibitor treatment. In this issue of the JCI, Oh, Wang, et al. report on the impact of Pol θ inhibition on activation of antitumor immunity. The authors used pancreatic ductal adenocarcinoma (PDAC) cell and mouse models characterized by HR-associated gene alterations and POLQ overexpression. POLQ knockdown showed synthetic lethality in combination with gene mutations involving DNA repair, including BRCA1, BRCA2, and ATM. Notably, Pol θ deficiency or inhibition suppressed tumor growth, increased the accumulation of unrepaired DNA damage, and enhanced T cell infiltration via the cGAS/STING pathway. These findings suggest a broader scope for Pol θ inhibition in HR-deficient cancers.