Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1
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nihms-1714747.pdf
Description
Accepted version
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3.04 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Romero, Rodrigo
Sánchez-Rivera, Francisco J
Westcott, Peter MK
Mercer, Kim L
Bhutkar, Arjun
Muir, Alexander
González Robles, Tania J
Lamboy Rodríguez, Swanny
Liao, Laura Z
Ng, Sheng Rong
Date Issued
2020
Journal
Nature Cancer
Publisher
Springer Science and Business Media LLC
Citation
Romero, Rodrigo, Sánchez-Rivera, Francisco J, Westcott, Peter MK, Mercer, Kim L, Bhutkar, Arjun et al. 2020. "Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1." Nature Cancer, 1 (6).
Version
Author's final manuscript
Abstract
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. 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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1038/S43018-020-0071-1
