肺腺癌 (LUAD) 通常由 KRAS 突变驱动，占所有癌症死亡率的 7%。第一个等位基因特异性 KRAS 抑制剂最近在 LUAD 中获得批准，但临床益处受到内在和获得性耐药性的限制。 LUAD 主要源自肺泡 2 型 (AT2) 细胞，其通过自我更新和替代肺泡 1 型 (AT1) 细胞发挥兼性肺泡干细胞的作用。使用基因工程小鼠模型、患者来源的异种移植物和患者样本，我们发现 KRAS 的抑制促进 LUAD 肿瘤中向静止 AT1 样癌细胞状态的转变。同样，抑制 Kras 会诱导野生型 AT2 细胞在肺损伤时发生 AT1 分化。 AT1 样 LUAD 细胞在治疗停止后表现出高生长和分化潜力，而 AT1 样细胞的消融则显着改善了对 KRAS 抑制剂的治疗反应。我们的结果揭示了 KRAS 在促进肿瘤内异质性方面的意想不到的作用，并表明针对肺泡分化可能会增强 LUAD 中的 KRAS 靶向治疗。

Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intra-tumoral heterogeneity and suggest targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD.