Study on Synthetic Lethal Target of DNA Damage Repair Related Pathways and Its Application and Prospect in Ovarian Cancer
10.13865/j.cnki.cjbmb.2024.03.1306
- VernacularTitle:DNA损伤修复相关通路的合成致死靶点研究及其在卵巢癌中的应用和前景
- Author:
Hong-Yan CHEN
1
;
Wen-Qing LUAN
;
Xiao-Hong CHANG
Author Information
1. 北京大学人民医院妇产科,北京 100044;北京大学人民医院妇科肿瘤中心,北京 100044
- Keywords:
ovarian cancer;
DNA damage response(DDR);
DNA damage repair;
PARP inhibitor(PARPi);
synthetic lethal;
targeted therapy
- From:
Chinese Journal of Biochemistry and Molecular Biology
2024;40(6):740-748
- CountryChina
- Language:Chinese
-
Abstract:
DNA damage triggers cells to initiate a series of DNA damage response(DDR),including DNA damage repair,cell cycle checkpoint activation,cell cycle arrest,activation of various intracellular signal transduction pathways,and cell apoptosis,etc.DNA Damage Repair,an important mechanism by which cells maintain genomic stability,was awarded the Nobel Prize in Chemistry in 2015.DNA damage repair pathways mainly include:base-excision repair(BER),nucleotide excision repair(NER),mis-match repair(MMR),homologous recombination(HR)and non-homologous end joining(NHEJ).They play an important role in the repair of DNA damage such as single-strand break(SSB)or double-strand break(DSB).DNA damage repair defects are closely related to tumorigenesis and development and is also an important target for tumor therapy.Poly-ADP-ribose polymerase(PARP)and breast canc-er susceptibility gene BRCA1/2 and others in the DNA damage repair pathways have synthetic lethality effects.It makes PARP inhibitor(PARPi)be the first and currently the only commercially available syn-thetic lethal target drug for tumor therapy.PARPi has good efficacy in the treatment of ovarian cancer and a variety of solid tumors,which make the research and development of synthetic lethal target drugs related to DNA damage repair and DDR pathway become a hot spot.Other targets under research mainly in-clude:ataxia telangiectasia-mutated protein(ATM),ataxia telangiectasia and RAD3 related protein(ATR),DNA-dependent protein kinase catalytic subunit(DNA-PKcs),checkpoint kinasel(CHK1),Checkpoint kinase 2(CHK2),mitogen-preventing protein kinase WEE 1,etc.The combination of PARPi with other DDR target drugs,anti-angiogenesis drugs or immune checkpoint inhibitors may be-come effective means and development prospect to overcome PARPi resistance and improve the therapeu-tic effect.Here we review the key molecules and potential tumor therapeutic targets in DNA damage re-pair and related DDR pathways,and the research on synthetic lethal targets and their application and prospect in ovarian cancer.We aim to provide guidance for basic research and clinical application.
