期刊
ADVANCED SCIENCE
卷 6, 期 17, 页码 -出版社
WILEY
DOI: 10.1002/advs.201900782
关键词
CRISPR-Cas9 libraries; E2F6; glioblastoma (GBM); temozolomide (TMZ) resistance
资金
- National Natural Science Foundation of China [81772667]
- Beijing Tianjin Hebei basic research cooperation project [18JCZDJC45500, H2018201306]
- Hebei Province technical innovation guidance funded projects of China [18247792D]
- Tianjin Municipal Science and Technology Commission Project [15ZXLCSY00060, 15ZXJZSY00040]
Amplification of epidermal growth factor receptor (EGFR) and active mutant EGFRvIII occurs frequently in glioblastoma (GBM) and contributes to cherno/radio-resistance in various cancers, especially in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in GBM could benefit cancer patients. A genome-wide screening under a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 library is conducted to identify the genes that confer resistance to TMZ in EGFRvIII-expressing GBM cells. Deep sgRNA sequencing reveals 191 candidate genes that are responsible for TMZ resistance in EGFRvIII-expressing GBM cells. Notably, E2F6 is proven to drive a TMZ resistance, and E2F6 expression is controlled by the EGFRvIII/AKT/NF-kappa B pathway. Furthermore, E2F6 is shown as a promising therapeutic target for TMZ resistance in orthotopic GBM cell line xenografts and GBM patient-derived xenografts models. After integrating clinical data with paired primary-recurrent RNA sequencing data from 134 GBM patients who received TMZ treatment after surgery, it has been revealed that the E2F6 expression level is a predictive marker for TMZ response. Therefore, the inhibition of E2F6 is a promising strategy to conquer TMZ resistance in GBM.
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