1Department of Translational Genomics; 2Institute of Pathology; 3Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne; 4Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany; and 5Michael F. Price Center, Albert Einstein College of Medicine, Bronx, New York.
Cancer Discov. 2014 May;4(5):592-605. doi: 10.1158/2159-8290.CD-13-0907. Epub 2014 Feb 20.
Here, we use a large-scale cell line-based approach to identify cancer cell-specific mutations that are associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) dependence. For this purpose, we profiled the mutational landscape across 1,319 cancer-associated genes of 67 distinct cell lines and identified numerous genes involved in homologous recombination-mediated DNA repair, including BRCA1, BRCA2, ATM, PAXIP, and RAD50, as being associated with non-oncogene addiction to DNA-PKcs. Mutations in the mismatch repair gene MSH3, which have been reported to occur recurrently in numerous human cancer entities, emerged as the most significant predictors of DNA-PKcs addiction. Concordantly, DNA-PKcs inhibition robustly induced apoptosis in MSH3-mutant cell lines in vitro and displayed remarkable single-agent efficacy against MSH3-mutant tumors in vivo. Thus, we here identify a therapeutically actionable synthetic lethal interaction between MSH3 and the non-homologous end joining kinase DNA-PKcs. Our observations recommend DNA-PKcs inhibition as a therapeutic concept for the treatment of human cancers displaying homologous recombination defects.
在这里，我们采用大规模基于细胞系的方法来鉴定与 DNA 依赖性蛋白激酶催化亚基（DNA-PKcs）依赖性相关的癌细胞特异性突变。为此，我们对 67 种不同细胞系的 1319 个癌症相关基因进行了突变谱分析，并鉴定出许多参与同源重组介导的 DNA 修复的基因，包括 BRCA1、BRCA2、ATM、PAXIP 和 RAD50，它们与非致癌基因对 DNA-PKcs 的成瘾有关。错配修复基因 MSH3 的突变已被报道在许多人类癌症实体中反复发生，是 DNA-PKcs 成瘾的最显著预测因子。一致地，DNA-PKcs 抑制在体外强烈诱导 MSH3 突变细胞系中的细胞凋亡，并在体内对 MSH3 突变肿瘤显示出显著的单药疗效。因此，我们在这里确定了 MSH3 和非同源末端连接激酶 DNA-PKcs 之间具有治疗作用的合成致死相互作用。我们的观察结果推荐 DNA-PKcs 抑制作为治疗具有同源重组缺陷的人类癌症的治疗概念。
