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A Pancreas Organoids-based Screen Identifies a Specific KRAS Mutation Inhibitor that Attenuating Cholesterol Biosynthesis Pathway in Pancreatic Cancer

ABSTRACT: we reported a high-content drug screening platform of a series of pancreas organoids which contain common mutations found in human pancreatic cancer, wide type (WT), KC (KRASG12D), KPC (KRASG12D; Tp53R172H), KSC (KRASG12D; SMAD4-/-) and KPSC (KRASG12D; Tp53R172H and SMAD4-/-). Based on this platform, we screened about 6000 compounds and identified Perhexiline, which can inhibit the growth of pancreas organoids with KRAS mutation in vitro and in vivo. Single cell RNA-seq data shows that the cholesterol synthesis pathway is activated specifically caused by KRAS in mutated organoid lines. The key cholesterol synthesis regulator of SREBP2 and its downstream genes are activated in KRAS mutated organoids compared with WT. Interestingly, Perhexiline can reverse the metabolism changes in pancreas organoids with KRAS through downregulating SREBP2 at transcription level. Finally, we further validated targeting SREBP2 can attenuate tumor growth significantly with chemical inhibitor and genetic perturbation. These findings boost further understanding of KRAS in PDAC and provide a valuable resource for targeting KRAS therapeutics development.

ORGANISM(S): Mus musculus

PROVIDER: GSE207352 | GEO | 2023/11/16

REPOSITORIES: GEO

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