KRASG12C and KRASG12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms. We contrasted tumor development between KrasG12C and KrasG12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of KrasG12C and KrasG12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRASG12C or KRASG12D-mutant NSCLC. KRASG12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRASG12D GEMMs compared to KRASG12C. This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRASG12C oncogenicity and downstream pathway activation were comparable with KRASG12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRASG12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRASG12C models on the MAPK pathway. Specifically, KRASG12D inhibition was enhanced by AKT inhibition in vitro and in vivo. Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.

中文翻译：

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PI3K-AKT-mTOR 轴在 KRASG12D 驱动的非小细胞肺癌中作为治疗依赖性持续存在


KRASG12C 和 KRASG12D 抑制剂通过直接靶向其突变最严重的癌蛋白，代表了非小细胞肺癌 （NSCLC） 和一般癌症的重大转化突破。然而，对这些小分子的耐药性凸显了对合理组合伴侣的需求，因此需要对 KRAS 突变亚型下游的信号转导进行批判性理解。我们对比了 KrasG12C 和 KrasG12D 基因工程小鼠模型 （GEMMs） 之间的肿瘤发展。为了证实研究结果并确定突变亚型特异性依赖性，通过 RNA 测序分析 KrasG12C 和 KrasG12D 起始和适应的同基因模型。我们还采用了已建立的 KRAS 突变 NSCLC 的细胞系模型，并通过药物抑制确定了治疗脆弱性。我们分析了晚期 KRASG12C 或 KRASG12D 突变 NSCLC 患者生存结局的差异。KRASG12D 在体内表现出更高的效力，与 KRASG12C 相比，表现为肺肿瘤形成更快，KRASG12D GEMM 的存活率降低。这种增加的效力，在同基因起始模型中概括，与增强的 PI3K-AKT-mTOR 信号传导有关。然而，KRASG12C致癌性和下游途径激活与体外和体内肿瘤发生后期的 KRASG12D相当，与患者的相似临床结局一致。尽管如此，已建立的 KRASG12D NSCLC 模型更多地依赖于 PI3K-AKT-mTOR 通路，而KRASG12C模型依赖于 MAPK 通路。具体来说，KRASG12D 抑制在体外和体内通过 AKT 抑制而增强。 我们的数据突出了独特的联合治疗脆弱性，并建议使用直接 KRAS 抑制剂的联合方法的患者选择策略应 i） 针对单个 RAS 突变体，以及 ii） 针对其下游信号传导量身定制。