Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair

被引：167

作者：

Lu, Yanxin ^{[1
]}

Kwintkiewicz, Jakub ^{[2
,3
]}

Liu, Yang ^{[1
]}

Tech, Katherine ^{[4
]}

Frady, Lauren N. ^{[2
,3
]}

Su, Yu-Ting ^{[1
]}

Bautista, Wendy ^{[1
]}

Moon, Seog In ^{[1
]}

MacDonald, Jeffrey ^{[4
]}

Ewend, Matthew G. ^{[2
,3
]}

Gilbert, Mark R. ^{[1
]}

Yang, Chunzhang ^{[1
]}

Wu, Jing ^{[1
,2
,3
]}

机构：

[1] NCI, Neurooncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA

[2] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA

[3] Univ North Carolina Chapel Hill, Dept Neurosurg, Chapel Hill, NC USA

[4] Univ North Carolina Chapel Hill, Sch Med, Dept Biomed Engn, Chapel Hill, NC USA

来源：

CANCER RESEARCH | 2017年 / 77卷 / 07期

关键词：

MUTANT IDH1; ISOCITRATE DEHYDROGENASE; OLIGODENDROGLIAL TUMORS; ADJUVANT TEMOZOLOMIDE; GLIOBLASTOMA CELLS; PHASE-III; MUTATIONS; CANCER; INHIBITOR; SURVIVAL;

D O I：

10.1158/0008-5472.CAN-16-2773

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival. In the present study, we found that defects in oxidative metabolism and 2-HG production confer chemosensitization in IDH1-mutated glioma cells. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells. The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD_ availability. Targeting the PARP DNA repair pathway extensively sensitized IDH1-mutated glioma cells to TMZ. Our findings demonstrate a novel molecular mechanism that defines chemosensitivity in IDH-mutated gliomas. Targeting PARP-associated DNA repair may represent a novel therapeutic strategy for gliomas.

引用

页码：1709 / 1718

页数：10

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