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

被引：31

作者：

Duan, Xiaohua ^{[1
,2
]}

Zhang, Tuo ^{[3
]}

Feng, Lingling ^{[1
,4
]}

de Silva, Neranjan ^{[1
]}

Greenspun, Benjamin ^{[1
,2
]}

Wang, Xing ^{[5
]}

Moyer, Jenna ^{[5
]}

Martin, M. Laura ^{[5
]}

Chandwani, Rohit ^{[1
,6
]}

Elemento, Olivier ^{[5
]}

Leach, Steven D. ^{[7
]}

Evans, Todd ^{[1
,2
]}

Chen, Shuibing ^{[1
,2
]}

Pan, Fong Cheng ^{[1
]}

机构：

[1] Weill Cornell Med, Dept Surg, 1300 York Ave, New York, NY 10065 USA

[2] Weill Cornell Med, Ctr Genom Hlth, 1300 York Ave, New York, NY 10065 USA

[3] Weill Cornell Med, Genom Resources Core Facil, New York, NY 10065 USA

[4] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol CCNU, Minist Educ, Wuhan 430079, Hubei, Peoples R China

[5] Weill Cornell Med, Caryl & Israel Englander Inst Precis Med, New York, NY USA

[6] Sandra & Edward Meyer Canc Ctr, Weill Cornell Med, New York, NY 10065 USA

[7] Dartmouth Coll, Dartmouth Canc Ctr, Hanover, NH 03755 USA

来源：

CELL STEM CELL | 2024年 / 31卷 / 01期

关键词：

MEVALONATE PATHWAY; MOLECULAR SUBTYPES; GENE-EXPRESSION; DRUG RESPONSE; LONG-TERM; IN-VITRO; TUMOR; CHOLESTEROL; MODELS; SREBP;

D O I：

10.1016/j.stem.2023.11.011

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页码：71 / 88.e8

页数：27

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