KRAS mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. The success of drugs targeting KRAS suggests the potential for drugs specifically targeting these alternative PDAC-associated KRAS mutations. Here, we report a high-throughput drug-screening platform using a series of isogenic murine pancreatic organoids that are wild type (WT) or contain common PDAC driver mutations, representing both classical and basal PDAC phenotypes. We screened over 6,000 compounds and identified perhexiline maleate, which can inhibit the growth and induce cell death of pancreatic organoids carrying the Kras mutation both and and primary human PDAC organoids. scRNA-seq analysis suggests that the cholesterol synthesis pathway is upregulated specifically in the KRAS mutant organoids, including the key cholesterol synthesis regulator SREBP2. Perhexiline maleate decreases SREBP2 expression levels and reverses the KRAS mutant-induced upregulation of the cholesterol synthesis pathway.

中文翻译：

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胰腺癌类器官平台鉴定出针对突变 KRAS 的特异性抑制剂

KRAS 突变，主要是 G12D 和 G12V，存在于超过 90% 的胰腺导管腺癌 (PDAC) 病例中。靶向 KRAS 药物的成功表明专门针对这些替代性 PDAC 相关 KRAS 突变的药物的潜力。在这里，我们报告了一个高通量药物筛选平台，使用一系列野生型（WT）或包含常见 PDAC 驱动突变的同基因小鼠胰腺类器官，代表经典和基础 PDAC 表型。我们筛选了 6,000 多种化合物，并鉴定出了马来酸哌克昔林，它可以抑制携带 Kras 突变的胰腺类器官和原代人 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。Perhexilinemaleate 降低 SREBP2 表达水平并逆转 KRAS 突变体诱导的胆固醇合成途径上调。