胰腺导管腺癌 (PDAC) 的肿瘤内异质性的特点是基础和经典上皮癌细胞状态之间的平衡，基础优势与化疗耐药和不良预后相关。靶向致癌 KRAS（胰腺癌的主要驱动因素）在临床试验中显示出早期前景，但疗效受到获得性耐药的限制。使用基因工程小鼠模型和患者来源的异种移植物，我们发现基底 PDAC 细胞对 KRAS 抑制剂高度敏感。利用荧光和生物发光报告系统，我们纵向追踪体内细胞状态动态，并揭示 KRAS 抑制剂诱导的经典状态的快速富集。谱系追踪发现这些富集的经典 PDAC 细胞是疾病复发的储存库。经典细胞状态的基因消除与 KRAS 抑制具有协同作用，为这种治疗策略提供了临床前概念验证。我们的研究结果促使将经典状态定向疗法与 KRAS 抑制剂相结合，以加深胰腺癌的反应并抵消耐药性。

Intra-tumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with basal dominance associating with chemoresistance and a dismal prognosis. Targeting oncogenic KRAS, the primary driver of pancreatic cancer, shows early promise in clinical trials but efficacy is limited by acquired resistance. Using genetically engineered mouse models and patient-derived xenografts, we find that basal PDAC cells are highly sensitive to KRAS inhibitors. Employing fluorescent and bioluminescent reporter systems, we longitudinally track cell-state dynamics in vivo and reveal a rapid, KRAS inhibitor-induced enrichment of the classical state. Lineage-tracing identifies these enriched classical PDAC cells to be a reservoir for disease relapse. Genetic ablation of the classical cell-state is synergistic with KRAS inhibition, providing a pre-clinical proof-of-concept for this therapeutic strategy. Our findings motivate combining classical-state directed therapies with KRAS inhibitors to deepen responses and counteract resistance in pancreatic cancer.