突变体
生物
清脆的
遗传学
突变
遗传筛选
可药性
计算生物学
基因组编辑
基因
基因组
癌症研究
作者
Rodrigo Romero,Francisco J. Sánchez‐Rivera,Peter M.K. Westcott,Kim L. Mercer,Arjun Bhutkar,Alexander Muir,Tania J. González Robles,Swanny Lamboy Rodríguez,Laura Z. Liao,Sheng Rong Ng,Leanne Li,Caterina I. Colón,Santiago Naranjo,Mary C. Beytagh,Caroline A. Lewis,Peggy P. Hsu,Roderick T. Bronson,Matthew G. Vander Heiden,Tyler Jacks
出处
期刊:Nature cancer
[Springer Nature]
日期:2020-06-08
卷期号:1 (6): 589-602
被引量:43
标识
DOI:10.1038/s43018-020-0071-1
摘要
Approximately 20–30% of human lung adenocarcinomas (LUADs) harbor mutations in Kelch-like ECH-associated protein 1 (KEAP1) that hyperactivate the nuclear factor, erythroid 2-like 2 (NFE2L2) antioxidant program. We previously showed that Kras-driven Keap1-mutant LUAD is highly aggressive and dependent on glutaminolysis. Here we performed a druggable genome CRISPR screen and uncovered a Keap1-mutant-specific dependency on solute carrier family 33 member 1 (Slc33a1), as well as several functionally related genes associated with the unfolded protein response. Genetic and biochemical experiments using mouse and human Keap1-mutant tumor lines, as well as preclinical genetically engineered mouse models, validate Slc33a1 as a robust Keap1-mutant-specific dependency. Furthermore, unbiased genome-wide CRISPR screening identified additional genes related to Slc33a1 dependency. Overall, our study provides a rationale for stratification of patients harboring KEAP1-mutant or NRF2-hyperactivated tumors as likely responders to targeted SLC33A1 inhibition and underscores the value of integrating functional genetic approaches with genetically engineered mouse models to identify and validate genotype-specific therapeutic targets. A druggable genome CRISPR-Cas9 screen followed by functional validation in preclinical lung cancer models uncovers Slc33a1 as a Keap1-mutant-specific targetable dependency.
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