美国威尔康奈尔医学研究所Fong Cheng Pan等研究人员合作发现，胰腺癌类器官平台揭示一种针对突变型KRAS的特异性抑制剂。这一研究成果于2023年12月26日在线发表在国际学术期刊《细胞—干细胞》上。

研究人员报告了一个高通量药物筛选平台，该平台使用了一系列野生型（WT）或含有常见PDAC驱动基因突变的等基因小鼠胰腺类器官，代表了经典和基础胰腺导管腺癌（PDAC）表型。研究人员筛选了6000多种化合物，发现了马来酸哌克昔林，它能在体外和体内抑制携带Kras^G12D突变的胰腺类器官以及原发性人类PDAC类器官的生长并诱导细胞死亡。

scRNA-seq分析表明，胆固醇合成途径在KRAS突变类器官中特异性上调，包括关键的胆固醇合成调节因子SREBP2。马来酸哌克昔林降低了SREBP2的表达水平，并逆转了KRAS突变体诱导的胆固醇合成途径上调。

据了解，90%以上的PDAC病例都存在KRAS突变，主要是G12D和G12V。靶向KRAS^G12C的药物取得了成功，这表明特异性靶向这些PDAC相关KRAS突变的药物大有可为。

附：英文原文

Title: A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS

Author: Xiaohua Duan, Tuo Zhang, Lingling Feng, Neranjan de Silva, Benjamin Greenspun, Xing Wang, Jenna Moyer, M. Laura Martin, Rohit Chandwani, Olivier Elemento, Steven D. Leach, Todd Evans, Shuibing Chen, Fong Cheng Pan

Issue&Volume: 2023-12-26

Abstract: KRAS mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductaladenocarcinoma (PDAC) cases. The success of drugs targeting KRASG12C suggests the potential for drugs specifically targeting these alternative PDAC-associatedKRAS mutations. Here, we report a high-throughput drug-screening platform using aseries of isogenic murine pancreatic organoids that are wild type (WT) or containcommon PDAC driver mutations, representing both classical and basal PDAC phenotypes.We screened over 6,000 compounds and identified perhexiline maleate, which can inhibitthe growth and induce cell death of pancreatic organoids carrying the KrasG12D mutation both in vitro and in vivo and primary human PDAC organoids. scRNA-seq analysis suggests that the cholesterolsynthesis pathway is upregulated specifically in the KRAS mutant organoids, includingthe key cholesterol synthesis regulator SREBP2. Perhexiline maleate decreases SREBP2expression levels and reverses the KRAS mutant-induced upregulation of the cholesterolsynthesis pathway.

DOI: 10.1016/j.stem.2023.11.011

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00411-3