生物
MAPK/ERK通路
基因
遗传学
突变体
基因表达谱
清脆的
神经母细胞瘤RAS病毒癌基因同源物
癌症研究
细胞生物学
激酶
突变
基因表达
克拉斯
作者
Takahiro Ito,M. J. L. Young,Ruitong Li,Sidharth Jain,Andreas Wernitznig,John M. Krill-Burger,Christopher T. Lemke,Davide Monducci,Diego J. Rodriguez,Liang Chang,Sanjukta Dutta,Debjani Pal,Brenton R. Paolella,Michael Rothberg,David E. Root,Cory M. Johannessen,Laxmi Parida,Gad Getz,Francisca Vázquez,John G. Doench,Mahdi Zamanighomi,William R. Sellers
出处
期刊:Nature Genetics
[Springer Nature]
日期:2021-12-01
卷期号:53 (12): 1664-1672
被引量:61
标识
DOI:10.1038/s41588-021-00967-z
摘要
Although single-gene perturbation screens have revealed a number of new targets, vulnerabilities specific to frequently altered drivers have not been uncovered. An important question is whether the compensatory relationship between functionally redundant genes masks potential therapeutic targets in single-gene perturbation studies. To identify digenic dependencies, we developed a CRISPR paralog targeting library to investigate the viability effects of disrupting 3,284 genes, 5,065 paralog pairs and 815 paralog families. We identified that dual inactivation of DUSP4 and DUSP6 selectively impairs growth in NRAS and BRAF mutant cells through the hyperactivation of MAPK signaling. Furthermore, cells resistant to MAPK pathway therapeutics become cross-sensitized to DUSP4 and DUSP6 perturbations such that the mechanisms of resistance to the inhibitors reinforce this mechanism of vulnerability. Together, multigene perturbation technologies unveil previously unrecognized digenic vulnerabilities that may be leveraged as new therapeutic targets in cancer.
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