Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany. Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
Clin Cancer Res. 2014 Dec 1;20(23):5882-7. doi: 10.1158/1078-0432.CCR-14-1165.
Disabling mutations in genome maintenance and DNA repair pathways are frequently observed in cancer. These DNA repair defects represent genetic aberrations that are specific to cancer cells and not present in healthy tissues. It is thought that these molecular defects produce a "mutator phenotype," which allows incipient cancer cells to accumulate additional cancer-promoting mutations. In recent years, our molecular understanding of DNA double-strand break (DSB) repair mechanisms has led to the development of targeted therapeutic approaches to selectively eradicate cancer cells that display defects in homologous recombination-mediated DNA DSB repair. These regimens for the treatment of homologous recombination-defective tumors predominantly aim at pharmacologically repressing the activity of PARP1, which is crucial for base excision repair, or to inhibit the nonhomologous end joining kinase DNA-PKcs (DNA-dependent protein kinase, catalytic subunit). Normal tissue can bypass PARP1- or DNA-PKcs inhibitor-induced genotoxic lesions via homologous recombination-mediated DNA DSB repair. In contrast, homologous recombination-defective cancer cells are unable to properly repair DNA DSBs, in the presence of PARP1 or DNA-PKcs inhibitors, ultimately leading to apoptotic cancer cell death.
在癌症中，经常观察到基因组维持和 DNA 修复途径的失活突变。这些 DNA 修复缺陷代表了特定于癌细胞的遗传异常，而不存在于健康组织中。人们认为这些分子缺陷产生了“突变表型”，使早期癌细胞能够积累额外的促进癌症的突变。近年来，我们对 DNA 双链断裂 (DSB) 修复机制的分子理解导致了靶向治疗方法的发展，以选择性地消灭显示同源重组介导的 DNA DSB 修复缺陷的癌细胞。这些用于治疗同源重组缺陷肿瘤的方案主要旨在通过药理学抑制 PARP1 的活性来抑制碱基切除修复，或抑制非同源末端连接激酶 DNA-PKcs（DNA 依赖性蛋白激酶，催化亚基）。正常组织可以通过同源重组介导的 DNA DSB 修复绕过 PARP1 或 DNA-PKcs 抑制剂诱导的遗传毒性损伤。相比之下，同源重组缺陷的癌细胞在 PARP1 或 DNA-PKcs 抑制剂存在的情况下无法正确修复 DNA DSB，最终导致凋亡的癌细胞死亡。
