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Genome-Wide CRISPR-Cas9 Screening Identifies NF-?B/E2F6 Responsible for EGFRvIII-Associated Temozolomide Resistance in Glioblastoma.


ABSTRACT: Amplification of epidermal growth factor receptor (EGFR) and active mutant EGFRvIII occurs frequently in glioblastoma (GBM) and contributes to chemo/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-?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.

SUBMITTER: Huang K 

PROVIDER: S-EPMC6724471 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Genome-Wide CRISPR-Cas9 Screening Identifies NF-κB/E2F6 Responsible for EGFRvIII-Associated Temozolomide Resistance in Glioblastoma.

Huang Kai K   Liu Xing X   Li Yansheng Y   Wang Qixue Q   Zhou Junhu J   Wang Yunfei Y   Dong Feng F   Yang Chao C   Sun Zhiyan Z   Fang Chuan C   Liu Chaoyong C   Tan Yanli Y   Wu Xudong X   Jiang Tao T   Kang Chunsheng C  

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20190724 17


Amplification of epidermal growth factor receptor (EGFR) and active mutant EGFRvIII occurs frequently in glioblastoma (GBM) and contributes to chemo/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  ...[more]

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