Journal
ADVANCED SCIENCE
Volume 6, Issue 17, Pages -Publisher
WILEY
DOI: 10.1002/advs.201900782
Keywords
CRISPR-Cas9 libraries; E2F6; glioblastoma (GBM); temozolomide (TMZ) resistance
Categories
Funding
- 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]
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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.
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