ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/067/SRR11266767/SRR11266767.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/063/SRR11266763/SRR11266763_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/065/SRR11266765/SRR11266765_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/053/SRR11266753/SRR11266753_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/052/SRR11266752/SRR11266752_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/051/SRR11266751/SRR11266751.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/061/SRR11266761/SRR11266761_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/045/SRR11266745/SRR11266745.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/046/SRR11266746/SRR11266746.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/060/SRR11266760/SRR11266760_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/054/SRR11266754/SRR11266754_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/064/SRR11266764/SRR11266764_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/064/SRR11266764/SRR11266764_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/062/SRR11266762/SRR11266762_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/049/SRR11266749/SRR11266749.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/058/SRR11266758/SRR11266758_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/052/SRR11266752/SRR11266752_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/056/SRR11266756/SRR11266756_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/050/SRR11266750/SRR11266750.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/053/SRR11266753/SRR11266753_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/047/SRR11266747/SRR11266747.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/061/SRR11266761/SRR11266761_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/059/SRR11266759/SRR11266759_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/058/SRR11266758/SRR11266758_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/057/SRR11266757/SRR11266757_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/066/SRR11266766/SRR11266766.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/048/SRR11266748/SRR11266748.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/055/SRR11266755/SRR11266755.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/054/SRR11266754/SRR11266754_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/057/SRR11266757/SRR11266757_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/056/SRR11266756/SRR11266756_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/059/SRR11266759/SRR11266759_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/060/SRR11266760/SRR11266760_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/063/SRR11266763/SRR11266763_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/062/SRR11266762/SRR11266762_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR112/065/SRR11266765/SRR11266765_1.fastq.gzprimaryOK200GenomicsMassachusetts Institute of Technologyhttps://www.ebi.ac.uk/ena/browser/view/PRJNA611102Approximately 20-30% of human lung adenocarcinomas (LUAD) harbor loss-of-function (LOF) mutations in Kelch-like ECH Associated-Protein 1 (KEAP1), which lead to hyperactivation of the antioxidant program downstream from the nuclear factor, erythroid 2-like 2 (NRF2) transcription factor and correlates with poor prognosis. We previously showed that Keap1 mutation accelerates KRAS-driven LUAD and produces a marked dependency on glutaminolysis4. To extend the investigation of genetic dependencies in the context of Keap1 mutation, we performed a druggable genome CRISPR-Cas9 screen in Keap1-mutant cells. This analysis uncovered a Keap1-mutant-specific dependency on solute carrier family 33 member 1 (Slc33a1), an endomembrane-associated protein with roles in autophagy regulation5, as well as a series of functionally-related genes implicated in the unfolded protein response. Targeted genetic and biochemical experiments using mouse and human Keap1-mutant tumor lines, as well as preclinical genetically-engineered mouse models (GEMMs) of LUAD, 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 strong 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 GEMMs to identify and validate genotype-specific therapeutic targets.ENAfalseKeap1 deficiency results in a genotype-specific dependency on Slc33a12023-05-192020-04-17PRJNA611102