Oncogenic KRAS is a major driver in lung adenocarcinoma (LUAD) that has yet to be therapeutically conquered. Here we report that the SLC7A11/glutathione axis displays metabolic synthetic lethality with oncogenic KRAS. Through metabolomics approaches, we found that mutationally activated KRAS strikingly increased intracellular cystine levels and glutathione biosynthesis. SLC7A11, a cystine/glutamate antiporter conferring specificity for cystine uptake, was overexpressed in patients with KRAS-mutant LUAD and showed positive association with tumor progression. Furthermore, SLC7A11 inhibition by either genetic depletion or pharmacological inhibition with sulfasalazine resulted in selective killing across a panel of KRAS-mutant cancer cells in vitro and tumor growth inhibition in vivo, suggesting the functionality and specificity of SLC7A11 as a therapeutic target. Importantly, we further identified a potent SLC7A11 inhibitor, HG106, that markedly decreased cystine uptake and intracellular glutathione biosynthesis. Furthermore, HG106 exhibited selective cytotoxicity toward KRAS-mutant cells by increasing oxidative stress– and ER stress–mediated cell apoptosis. Of note, treatment of KRAS-mutant LUAD with HG106 in several preclinical lung cancer mouse models led to marked tumor suppression and prolonged survival. Overall, our findings reveal that KRAS-mutant LUAD cells are vulnerable to SLC7A11 inhibition, offering potential therapeutic approaches for this currently incurable disease.

中文翻译：

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SLC7A11 /谷胱甘肽轴的抑制导致KRAS突变型肺腺癌的合​​成致死性。

致癌性KRAS是尚未被治疗的肺腺癌（LUAD）的主要驱动力。在这里，我们报告SLC7A11 /谷胱甘肽轴显示致癌性KRAS的代谢合成杀伤力。通过代谢组学方法，我们发现突变激活的KRAS显着增加了细胞内胱氨酸水平和谷胱甘肽的生物合成。SLC7A11是一种赋予胱氨酸摄取特异性的胱氨酸/谷氨酸逆转运蛋白，在KRAS突变型LUAD患者中过表达，并与肿瘤进展呈正相关。此外，通过遗传耗竭或柳氮磺胺吡啶的药理抑制作用抑制SLC7A11会导致一系列KRAS的选择性杀伤体外突变的癌细胞和体内的肿瘤生长抑制，提示SLC7A11作为治疗靶点的功能和特异性。重要的是，我们进一步确定了有效的SLC7A11抑制剂HG106，该抑制剂可显着降低胱氨酸的摄取和细胞内谷胱甘肽的生物合成。此外，HG106通过增加氧化应激和ER应激介导的细胞凋亡，表现出对KRAS突变细胞的选择性细胞毒性。值得注意的是，在几种临床前肺癌小鼠模型中用HG106治疗KRAS突变型LUAD导致明显的肿瘤抑制和延长的生存期。总体而言，我们的发现表明，KRAS突变的LUAD细胞易受SLC7A11抑制，为这种目前无法治愈的疾病提供了潜在的治疗方法。