KRAS is among the most commonly mutated oncogenes in human malignancies. Although the advent of sotorasib and adagrasib, has lifted the “undruggable” stigma of KRAS, the resistance to KRAS inhibitors quickly becomes a major issue. Here, we reported that aldehyde dehydrogenase 1 family member A1 (ALDH1A1), an enzyme in retinoic acid biosynthesis and redox balance, increases in response to KRAS inhibitors and confers resistance in a range of cancer types. KRAS inhibitors' efficacy is significantly improved in sensitive or drug-resistant cells, patient-derived organoids (PDO), and xenograft models by ALDH1A1 knockout, loss of enzyme function, or inhibitor. Furthermore, we discovered that ALDH1A1 suppresses the efficacy of KRAS inhibitors by counteracting ferroptosis. ALDH1A1 detoxicates deleterious aldehydes, boosts the synthesis of NADH and retinoic acid (RA), and improves RARA function. ALDH1A1 also activates the CREB1/GPX4 pathway, stimulates the production of lipid droplets in a pH-dependent manner, and subsequently prevents ferroptosis induced by KRAS inhibitors. Meanwhile, we established that GTF2I is dephosphorylated at S784 via ERK by KRAS inhibitors, which hinders its nuclear translocation and mediates ALDH1A1's upregulation in response to KRAS inhibitors. In summary, the results offer valuable insights into targeting ALDH1A1 to enhance the effectiveness of KRAS-targeted therapy through ferroptosis in cancer treatment.

中文翻译：

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靶向ALDH1A1通过铁死亡增强 KRAS 靶向治疗的疗效


KRAS 是人类恶性肿瘤中最常见的突变癌基因之一。尽管 sotorasib 和 adagrasib 的出现消除了 KRAS 的“不可成药”耻辱，但对 KRAS 抑制剂的耐药性很快成为一个主要问题。在这里，我们报道了醛脱氢酶 1 家族成员 A1 （ALDH1A1） 是视黄酸生物合成和氧化还原平衡的一种酶，响应 KRAS 抑制剂而增加，并在一系列癌症类型中产生耐药性。KRAS 抑制剂在敏感或耐药细胞、患者来源类器官 （PDO） 和异种移植模型中的疗效通过ALDH1A1敲除、酶功能丧失或抑制剂而显著提高。此外，我们发现 ALDH1A1 通过对抗铁死亡来抑制 KRAS 抑制剂的疗效。ALDH1A1 对有害醛类起毒，促进 NADH 和视黄酸 （RA） 的合成，并改善 RARA 功能。ALDH1A1 还激活 CREB1/GPX4 通路，以 pH 依赖性方式刺激脂滴的产生，随后防止 KRAS 抑制剂诱导的铁死亡。同时，我们确定 GTF2I 在 S784 位点通过 ERK 被 KRAS 抑制剂去磷酸化，这阻碍了其核易位并介导 ALDH1A1 响应 KRAS 抑制剂的上调。总之，这些结果为靶向ALDH1A1以提高癌症治疗中通过铁死亡进行 KRAS 靶向治疗的有效性提供了有价值的见解。