尽管 EGFR 突变型肺腺癌的临床结果显着改善，但所有患者对 EGFR 酪氨酸激酶抑制剂 (EGFR-TKI) 的治疗都会产生获得性耐药和恶性肿瘤。了解耐药机制对于发现新的治疗靶点以提高 EGFR-TKI 治疗的疗效至关重要。在这里，使用 RNA-Seq 和 shRNA 代谢筛选的综合分析表明，谷胱甘肽 S-转移酶 omega 1 (GSTO1) 是肺腺癌细胞 EGFR-TKI 耐药所需的关键代谢酶之一。 GSTO1 的异常上调会赋予 EGFR-TKIs 耐药性，并且体外和体内肿瘤转移取决于其活性位点半胱氨酸 32 (C32)。 GSTO1 的药理抑制或敲低可恢复对 EGFR-TKI 的敏感性并协同增强杀肿瘤作用。重要的是，核磷蛋白 1 (NPM1) 半胱氨酸 104 被 GSTO1 通过其活性 C32 位点去谷胱甘肽，从而激活 AKT/NF-κB 信号通路。此外，临床数据表明GSTO1水平与NPM1水平、NF-κB介导的转录和人肺腺癌的进展呈正相关。总体而言，我们的研究强调了 GSTO1 通过蛋白去谷胱甘肽介导 EGFR-TKIs 耐药和恶性进展的新机制，以及 GSTO1/NPM1/AKT/NF-κB 轴作为肺腺癌潜在治疗脆弱性。© 2024。 ，获得施普林格自然有限公司的独家许可。

Despite significantly improved clinical outcomes in EGFR-mutant lung adenocarcinoma, all patients develop acquired resistance and malignancy on the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Understanding the resistance mechanisms is crucial to uncover novel therapeutic targets to improve the efficacy of EGFR-TKI treatment. Here, integrated analysis using RNA-Seq and shRNAs metabolic screening reveals glutathione S-transferase omega 1 (GSTO1) as one of the key metabolic enzymes that is required for EGFR-TKIs resistance in lung adenocarcinoma cells. Aberrant upregulation of GSTO1 confers EGFR-TKIs resistance and tumor metastasis in vitro and in vivo dependent on its active-site cysteine 32 (C32). Pharmacological inhibition or knockdown of GSTO1 restores sensitivity to EGFR-TKIs and synergistically enhances tumoricidal effects. Importantly, nucleophosmin 1 (NPM1) cysteine 104 is deglutathionylated by GSTO1 through its active C32 site, which leads to activation of the AKT/NF-κB signaling pathway. In addition, clinical data illustrates that GSTO1 level is positively correlated with NPM1 level, NF-κB-mediated transcriptions and progression of human lung adenocarcinoma. Overall, our study highlights a novel mechanism of GSTO1 mediating EGFR-TKIs resistance and malignant progression via protein deglutathionylation, and GSTO1/NPM1/AKT/NF-κB axis as a potential therapeutic vulnerability in lung adenocarcinoma.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.