文章：

在胰腺导管腺癌的临床前模型中使用KRAS抑制剂进行癌症拦截

Cancer interception with KRAS inhibitors in preclinical models of pancreatic ductal adenocarcinoma

原文发布日期：2026-03-12

DOI: 10.1126/science.aec7929

类型: Research Article

开放获取: 否

文章简介：

Editor’s summary

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and is frequently driven by mutations in the KRAS gene. Pancreatic intraepithelial neoplasias are precancerous precursor lesions of PDAC that typically harbor the KRAS activating mutation. Than et al. tested the effects of small-molecule KRAS inhibitor drugs as a chemopreventative strategy for pancreatic cancer (see the Perspective by Neel and Maitra). Using a well-studied model of pancreatic cancer, mice with pancreatic intraepithelial neoplasia lesions were treated with KRAS inhibitors before tumor formation. A series of different dosing regimens were tested, and early intervention was found to extend survival. Three-dimensional mapping of the tumor microenvironment suggested no major distortions in tissue architecture after treatment. The design of clinical trials to determine whether similar effects are observed in humans will be important next steps. —Priscilla N. Kelly

Abstract

Transformation of pancreatic epithelial cells to malignant pancreatic ductal adenocarcinoma (PDAC) typically involves the progression of precancerous pancreatic intraepithelial neoplasia (PanINs) bearing oncogenic KRAS mutations. Here, we tested the impact of PDAC interception using either RAS(ON) multiselective or RAS(ON) G12D-selective pharmacological inhibitors [RAS(ON) inhibitors] in mouse models of PDAC. Treatment of PanIN-bearing mice with RAS(ON) inhibitors prompted regression of premalignant lesions that translated into a delay in tumor onset and an increase in overall survival (OS). Long-term interception in tumor-prone mice resulted in a median OS of more than 1 year compared with less than 5 months in nonintercepted control mice (P < 0.0001). Comparing the survival benefits of RAS(ON) inhibition for cancer interception versus RAS(ON) inhibition for cancer treatment, we found that interception provided a greater survival benefit to mice. These findings suggest that a pharmacological approach may reduce premalignant burden and increase survival in PDAC.

简介翻译： 

编辑总结

胰腺导管腺癌（PDAC）是最常见的胰腺癌形式，通常由KRAS基因突变驱动。胰腺上皮内瘤变是PDAC的癌前病变前兆，通常携带KRAS激活突变。Than等人测试了小分子KRAS抑制剂药物作为胰腺癌化学预防策略的效果（参见Neel和Maitra的观点）。使用一个经过充分研究的胰腺癌模型，在肿瘤形成前，对患有胰腺上皮内瘤变的小鼠施用KRAS抑制剂进行治疗。测试了一系列不同的给药方案，发现早期干预可以延长生存期。肿瘤微环境的三维映射显示，治疗后组织结构没有发生重大扭曲。下一步的重要工作是设计临床试验以确定在人类中是否观察到类似效果。——Priscilla N. Kelly

摘要

胰腺上皮细胞向恶性胰腺导管腺癌（PDAC）的转化通常涉及携带致癌KRAS突变的癌前胰腺上皮内瘤变（PanINs）的进展。在此，我们在PDAC小鼠模型中测试了使用RAS(ON)多选择性或RAS(ON) G12D选择性药理抑制剂[RAS(ON)抑制剂]进行PDAC拦截的效果。用RAS(ON)抑制剂治疗携带PanIN的小鼠促使癌前病变消退，从而延缓肿瘤发生并提高总生存期（OS）。对易患肿瘤的小鼠进行长期拦截，中位OS超过1年，而未经拦截的对照组小鼠则不足5个月（P < 0.0001）。比较RAS(ON)抑制用于癌症拦截与RAS(ON)抑制用于癌症治疗的生存获益，我们发现拦截为小鼠提供了更大的生存获益。这些发现表明，药物干预方法可能减轻PDAC的癌前病变负担并提高生存率。

原文链接：

Cancer interception with KRAS inhibitors in preclinical models of pancreatic ductal adenocarcinoma