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.

大约 20-30% 的人类肺腺癌 (LUAD) 存在 Kelch 样 ECH 相关蛋白 1 ( KEAP1 ) 突变，该突变会过度激活核因子红细胞 2 样 2 ( NFE2L2 ) 抗氧化程序。我们之前表明Kras驱动的Keap1突变体 LUAD 具有高度攻击性并且依赖于谷氨酰胺分解。在这里，我们进行了可药物基因组 CRISPR 筛选，发现了对溶质载体家族 33 成员 1 ( Slc33a1 ) 的Keap1突变体特异性依赖性，以及与未折叠蛋白反应相关的几个功能相关基因。使用小鼠和人类Keap1突变肿瘤系以及临床前基因工程小鼠模型进行的遗传和生化实验验证了Slc33a1具有强大的Keap1突变特异性依赖性。此外，无偏见的全基因组 CRISPR 筛选还发现了与Slc33a1依赖性相关的其他基因。总体而言，我们的研究为将携带KEAP1突变或 NRF2 过度激活肿瘤的患者分层作为对靶向 SLC33A1 抑制的可能反应者提供了依据，并强调了将功能遗传方法与基因工程小鼠模型相结合以识别和验证基因型特异性治疗靶点的价值。