The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.

中文翻译：

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MAPK-SOX2 通路的再激活赋予 KRASG12C 抑制剂耐药肿瘤的铁死亡敏感性


包括 AMG510 和 MRTX849 在内的KRASG12C抑制剂 （G12Ci） 的临床成功受到最终获得性耐药发展的限制。一种新颖有效的治疗方法来恢复或针对这种耐药性是当务之急。为此，我们建立了 G12Ci （AMG510 和 MRTX849） 耐药KRASG12C突变癌细胞系，并使用 FDA 批准的药物库进行筛选。我们发现包括索拉非尼和拉帕替尼在内的铁死亡诱导剂在 G12Ci 耐药细胞中脱颖而出，具有明显的生长抑制作用。从机制上讲，G12Ci 抗性细胞表现出 MAPK 信号转导的重新激活，这抑制了 SOX2 介导的胱氨酸转运蛋白 SLC7A11 和铁输出蛋白 SLC40A1 的表达。因此，细胞内 GSH 水平低但铁含量高导致这些耐药肿瘤对铁死亡诱导剂过敏。SOX2 或 SLC7A11 和 SLC40A1 的异位过表达在 G12Ci 抗性细胞中赋予对铁死亡的抵抗力。柳氮磺吡啶 （SAS） 诱导的铁死亡对 AMG510 耐药 KRASG12C 突变细胞来源的异种移植物的肿瘤生长实现了明显抑制。总的来说，我们的研究结果提出了一种新的治疗策略，可以用铁死亡诱导剂治疗 G12Ci 耐药癌症患者。