Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1

• Main Authors: Romero, Rodrigo (Author), Sánchez-Rivera, Francisco J (Author), Westcott, Peter MK (Author), Mercer, Kim L (Author), Bhutkar, Arjun (Author), Muir, Alexander (Author), González Robles, Tania J (Author), Lamboy Rodríguez, Swanny (Author), Liao, Laura Z (Author), Ng, Sheng Rong (Author), Li, Leanne (Author), Colón, Caterina I (Author), Naranjo, Santiago (Author), Beytagh, Mary Clare (Author), Lewis, Caroline A (Author), Hsu, Peggy P (Author), Bronson, Roderick T (Author), Vander Heiden, Matthew G (Author), Jacks, Tyler (Author)
• Format: Article
• Language: English
• Published: Springer Science and Business Media LLC, 2021-10-25T18:57:39Z.
• Subjects: Article
• Online Access: Get fulltext

 © 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.