KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

中文翻译：

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胰腺癌中致癌 KRAS 抑制的抵抗机制


KRAS 抑制剂在胰腺导管腺癌 (PDAC) 中表现出临床疗效；然而，抵制是很常见的。在接受阿达格拉西或索托拉西治疗的 KRASG12C 突变 PDAC 患者中，获得性耐药时出现 PIK3CA 和 KRAS 突变以及 KRASG12C、MYC、MET、EGFR 和 CDK6 扩增。在用 KRASG12D 抑制剂 MRTX1133 处理的 PDAC 细胞系和类器官模型中，上皮间质转化和 PI3K-AKT-mTOR 信号传导与治疗耐药相关。 MRTX1133 治疗 KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) 小鼠模型使肿瘤深度消退，但最终出现耐药性，并伴随着 Kras、Yap1、Myc 和 Cdk6/Abcb1a/ 的扩增b、耐药转录程序的共同进化。此外，在 KPC 和 PDX 模型中，与经典状态相比，间充质和基底样细胞状态对 KRAS 抑制的反应增强。 KRASG12D 抑制和化疗的联合治疗显着改善了 PDAC 小鼠模型的肿瘤控制。总的来说，这些数据阐明了 KRAS 抑制的共同进化耐药机制，并支持多种联合治疗策略。