학술논문
Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1
Document Type
Original Paper
Author
Romero, Rodrigo; Sánchez-Rivera, Francisco J.; Westcott, Peter M. K.; Mercer, Kim L.; Bhutkar, Arjun; Muir, Alexander; González Robles, Tania J.; Lamboy Rodríguez, Swanny; Liao, Laura Z.; Ng, Sheng Rong; Li, Leanne; Colón, Caterina I.; Naranjo, Santiago; Beytagh, Mary Clare; Lewis, Caroline A.; Hsu, Peggy P.; Bronson, Roderick T.; Vander Heiden, Matthew G.; Jacks, Tyler
Source
Nature Cancer. 1(6):589-602
Subject
Language
English
ISSN
2662-1347
Abstract
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.
A druggable genome CRISPR-Cas9 screen followed by functional validation in preclinical lung cancer models uncovers Slc33a1 as a Keap1-mutant-specific targetable dependency.