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

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING
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
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Abstract

KRAS mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. The success of drugs targeting KRASG12C 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 KrasG12D mutation both in vitro and in vivo 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.

Abstract Image

胰腺癌类器官平台确定了一种针对突变型 KRAS 的特异性抑制剂
90%以上的胰腺导管腺癌(PDAC)病例都存在 KRAS 突变,主要是 G12D 和 G12V。靶向 KRASG12C 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。在此,我们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 驱动基因突变的同源小鼠胰腺器官组织,代表了经典和基础 PDAC 表型。我们筛选了 6,000 多种化合物,发现了马来酸哌西林,它能在体外和体内抑制携带 KrasG12D 突变的胰腺器官组织以及原发性人类 PDAC 器官组织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 突变器官组织中特异性上调,包括关键的胆固醇合成调节因子 SREBP2。马来酸培瑞西林降低了SREBP2的表达水平,逆转了KRAS突变体诱导的胆固醇合成途径上调。
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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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