Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1

• Published in: Nature cancer Vol. 1; no. 6; p. 589
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England 01.06.2020
• Subjects: Adenocarcinoma of Lung - genetics; Animals; Humans; Kelch-Like ECH-Associated Protein 1 - genetics; Lung Neoplasms - genetics; Membrane Transport Proteins - genetics; Mice; Mutation; NF-E2-Related Factor 2 - genetics
• ISSN: 2662-1347
• DOI: 10.1038/s43018-020-0071-1

Approximately 20-30% of human lung adenocarcinomas (LUAD) harbor loss-of-function (LOF) mutations in Kelch-like ECH Associated-Protein 1 ( ), which lead to hyperactivation of the nuclear factor, erythroid 2-like 2 (NRF2) antioxidant pathway and correlate with poor prognosis . We previously showed that mutation accelerates KRAS-driven LUAD and produces a marked dependency on glutaminolysis . To extend the investigation of genetic dependencies in the context of mutation, we performed a druggable genome CRISPR-Cas9 screen in -mutant cells. This analysis uncovered a profound mutant-specific dependency on solute carrier family 33 member 1 ( ), an endomembrane-associated protein with roles in autophagy regulation , as well as a series of functionally-related genes implicated in the unfolded protein response. Targeted genetic and biochemical experiments using mouse and human -mutant tumor lines, as well as preclinical genetically-engineered mouse models (GEMMs) of LUAD, validate as a robust -mutant-specific dependency. Furthermore, unbiased genome-wide CRISPR screening identified additional genes related to dependency. Overall, our study provides a strong rationale for stratification of patients harboring -mutant or NRF2-hyperactivated tumors as likely responders to targeted SLC33A1 inhibition and underscores the value of integrating functional genetic approaches with GEMMs to identify and validate genotype-specific therapeutic targets.