文章目录

Keap1突变使肺腺癌依赖于Slc33a1

原文发布日期：2020-06-08

英文摘要：

摘要翻译：

原文链接：

文章：

Keap1突变使肺腺癌依赖于Slc33a1

Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1

原文发布日期：2020-06-08

英文摘要：

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.

摘要翻译：

约20%-30%的人类肺癌腺癌（LUADs）携带KEAP1突变，这些突变使NFE2L2抗氧化应答超活化。我们之前显示，由KRAS驱动的KEAP1突变型LUAD具有高度的侵袭性和依赖于谷氨酰胺代谢。在此研究中，我们进行了可药代的组学CRISPR筛选，并揭示了KEAP1突变体特定地依赖于运输ersene家族成员1（Slc33a1），以及与 unfolded protein response（UPR）相关的几个功能相关基因。使用小鼠和人类KEAP1突变肿瘤细胞系，以及功能基因组学的前 clen 鼠模型进行遗传学及生化实验，证实了Slc33a1依赖性是可靠的KEAP1突变体特异性依赖。此外，在无偏 broaden genome-wide CRISPR筛选中，我们还发现了与Slc33a1依赖相关的其他基因。综上所述，本研究为携带KEAP1突变或NRF2超活化的肿瘤的患者分层提供了理由，并验证了针对SLC33A1抑制治疗的目标具有特定性；同时强调通过功能基因学方法结合功能基因组学小鼠模型来识别和验证目标基因型特异性治疗靶点的价值。