期刊
MOLECULAR CANCER RESEARCH
卷 17, 期 2, 页码 431-445出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-18-0594
关键词
-
资金
- Advanced Medical Research Foundation
- Vincent Memorial Research Funds
PARP inhibitors (PARPi) are FDA-approved monotherapy agents for the treatment of recurrent ovarian cancer in patients with and without a BRCA mutation. Despite promising response rates, not all patients derive benefit, and the majority develop resistance. PARPi treatment in vitro and in vivo induced an enrichment of CD133 thorn and CD117 thorn ovarian cancer stem cells (CSC). This effect was not affected by BRCA mutation status. In the CSC fractions, PARPi induced cell-cycle arrest in G2-M with a consequent accumulation of gH2AX, RAD51, and uniquely DMC1 foci. DNA damage and repair monitoring assays demonstrated that CSCs display more efficient DNA repair due, in part, to activation of embryonic repair mechanisms which involved the RAD51 homologue, DMC1 recombinase. Preserved and induced homologous repair (HR) could be a mechanism of an inherent resistance of CSCs to the synthetic lethality of PARPi that likely promotes disease recurrence. Implications: Treatment with PARPi fails to significantly affect ovarian cancer CSC populations, likely contributing to recurrent disease. Ovarian cancer CSCs stabilize genomic integrity after PARPi treatment, due to a more efficient inherent DNA repair capacity. PARPi-induced DMC1 recombinase and HR proficiency provide CSCs the opportunity to repair DNA damage more efficiently. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/2/431/F1.large.jpg.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据