DNA修复
DNA损伤修复
癌症研究
PARP抑制剂
奥拉帕尼
癌症
DNA损伤
合成致死
基因组不稳定性
聚ADP核糖聚合酶
PARP1
突变
体细胞
聚合酶
医学
软膜
生物
基底切除修复术
DNA
计算生物学
遗传学
基因
作者
Jessica Brown,Brent O’Carrigan,Stephen Jackson,Timothy A. Yap
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2017-01-01
卷期号:7 (1): 20-37
被引量:433
标识
DOI:10.1158/2159-8290.cd-16-0860
摘要
Abstract Germline aberrations in critical DNA-repair and DNA damage–response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair. We focus on novel therapeutic strategies targeting promising DDR targets and discuss challenges of patient selection and the development of rational drug combinations. Significance: Various inhibitors of DDR components are in preclinical and clinical development. A thorough understanding of DDR pathway complexities must now be combined with strategies and lessons learned from the successful registration of PARP inhibitors in order to fully exploit the potential of DDR inhibitors and to ensure their long-term clinical success. Cancer Discov; 7(1); 20–37. ©2016 AACR.
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