Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China.
Oncogene. 2024 Aug;43(33):2504-2516. doi: 10.1038/s41388-024-03096-z. Epub 2024 Jul 5.
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.
尽管表皮生长因子受体（EGFR）突变型肺腺癌的临床结局显著改善，但所有患者在接受 EGFR 酪氨酸激酶抑制剂（EGFR-TKIs）治疗后均会产生获得性耐药和恶性肿瘤。了解耐药机制对于揭示新的治疗靶点以提高 EGFR-TKI 治疗效果至关重要。在这里，使用 RNA-Seq 和 shRNA 代谢筛选的综合分析揭示了谷胱甘肽 S-转移酶ω 1（GSTO1）作为关键代谢酶之一，它是肺腺癌细胞中 EGFR-TKIs 耐药所必需的。GSTO1 的异常上调赋予了 EGFR-TKIs 耐药性，并依赖其活性半胱氨酸 32（C32）在体外和体内促进肿瘤转移。GSTO1 的药理学抑制或敲低可恢复对 EGFR-TKIs 的敏感性，并协同增强肿瘤杀伤作用。重要的是，核仁磷酸蛋白 1（NPM1）半胱氨酸 104 可被 GSTO1 通过其活性 C32 位点去谷胱甘肽化，从而导致 AKT/NF-κB 信号通路的激活。此外，临床数据表明，GSTO1 水平与 NPM1 水平、NF-κB 介导的转录和人类肺腺癌的进展呈正相关。总的来说，我们的研究强调了 GSTO1 通过蛋白去谷胱甘肽化介导 EGFR-TKIs 耐药和恶性进展的新机制，以及 GSTO1/NPM1/AKT/NF-κB 轴作为肺腺癌潜在的治疗弱点。
