KRAS inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting -mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with and / co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of -deficient and lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and . Notably, expression of the AST plasticity signature and at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

中文翻译：

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LKB1 突变肺癌中腺癌到鳞状细胞的转变导致对 KRAS 抑制的抵抗

KRAS 抑制剂（adagrasib 和 sotorasib）已显示出针对突变肺癌的临床前景；然而，大多数患者最终会产生耐药性。在患有 和 / 共突变的肺腺癌患者中，我们发现治疗前活检中鳞状细胞癌基因特征的富集与阿达拉西的不良反应相关。对 β-缺陷小鼠和肺癌小鼠模型以及用 KRAS 抑制剂治疗的类器官的研究表明，肿瘤会引发谱系可塑性程序，腺-鳞状细胞转变 (AST)，从而能够抵抗 KRAS 抑制。转录组和表观基因组分析表明 ΔNp63 驱动 AST 并调节对 KRAS 抑制的反应。我们确定了一种中间高可塑性细胞状态，其标志为 AST 可塑性特征的表达和 。值得注意的是，AST 可塑性特征和基线的表达与阿达拉西不良反应相关。这些数据表明 AST 在 KRAS 抑制剂耐药性中的作用，并为肺癌 KRAS 靶向治疗提供预测生物标志物。