期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-17717-0
关键词
-
资金
- Seve Ballesteros Foundation
- Asociacion Espanola Contra el Cancer (AECC)
- Natural Science Foundation of China (NSFC)/Research Grants Council (RGC) [81761168038, N_HKUST606/17]
- RGC-ECS [26102719]
- NSFC [31922088]
- ITC [ITCPD/17-9]
- Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support [ZYLX201708]
- Beijing Municipal Administration of Hospitals' Mission Plan [SML20180501]
- Beijing Nova Program [Z171100001117022]
- Beijing Talents Foundation from Organization department of Municipal committee of the CPC [2017000021223ZK32]
Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ. Chemotherapy resistance in recurrent gliomas is a large hurdle for successful therapy. Here, the authors show that some recurrent gliomas harbour O-6-methylguanine-DNA methyltransferase (MGMT) genomic rearrangements, and in vitro and in vivo these contribute to temozolomide resistance.
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