Pancreatic cancer is characterized by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered KRAS gene dosage drives progression and metastasis in pancreatic cancer. While the role of oncogenic KRAS mutations is well characterized, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrated that wild-type KRAS restrains the oncogenic impact of mutant KRAS and dramatically impacts both KRAS-mediated tumorigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increased oncogenic KRAS signaling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, lack of wild-type KRAS led to accelerated initiation but delayed tumor progression. These tumors had altered stroma and an enrichment of immunogenic gene signatures. Importantly, loss of wild-type Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of wild-type KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of wild-type KRAS in both tumor progression and therapeutic response in pancreatic cancer.

中文翻译：

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KRAS 杂合性缺失促进 MAPK 依赖性胰腺导管腺癌的发生，并诱导对 MEK 抑制的治疗敏感性


胰腺癌的特征是 KRAS 中癌变突变的普遍性。以前的研究报道，改变的 KRAS 基因剂量会驱动胰腺癌的进展和转移。虽然致癌 KRAS 突变的作用已得到充分表征，但配对野生型 KRAS 等位基因在胰腺癌中的相关性尚不清楚且存在争议。使用胰腺癌的体内小鼠模型，我们证明野生型 KRAS 抑制了突变 KRAS 的致癌影响，并显着影响 KRAS 介导的肿瘤发生和治疗反应。从机制上讲，野生型 Kras 的缺失通过下游 MAPK 效应子途径增加了致癌 KRAS 信号传导，从而驱动胰腺上皮内瘤变 （PanIN） 的启动。此外，在 KPC 小鼠模型中，一种更具侵袭性的胰腺癌模型，缺乏野生型 KRAS 导致加速启动但延迟了肿瘤进展。这些肿瘤具有改变的基质和免疫原性基因特征的富集。重要的是，野生型 Kras 的缺失使 Kras 突变肿瘤对 MEK1/2 抑制敏感，尽管肿瘤最终变得耐药并迅速进展。本研究证明了野生型 KRAS 在胰腺肿瘤发生过程中的抑制作用，并强调了野生型 KRAS 的存在对胰腺癌肿瘤进展和治疗反应的关键影响。