Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy

Summary

Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these reflect the molecular and phenotypic heterogeneity of primary PDAC tissue. We use CRISPR-Cas9 genome editing and drug screening to characterize drug-gene interactions with ARID1A and BRCA2. We find that missense, but not frameshift, mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib (p < 0.0001) and VE-821 (p < 0.0001). We further conduct an automated drug-repurposing screen with 1,172 FDA-approved compounds, identifying 26 compounds that effectively kill PDAC organoids, including 19 chemotherapy drugs currently approved for other cancer types. We validate the activity of these compounds in vitro and in vivo. The in vivo validated hits include emetine and ouabain, compounds that are approved for non-cancer indications and that perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and for identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks.

Graphical abstract

Highlights

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  Established biobank from 31 genetically distinct human PDAC organoid lines

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  Missense mutations in ARID1A increase sensitivity of PDAC to dastinib and VE-821

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  Automated drug screening identifies compounds that effectively kill PDAC organoids

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  Emetine and ouabain perturb the ability of PDAC cells to respond to hypoxia

Abstract

Hirt et al. established a human PDAC organoid biobank to study drug-gene interactions and perform high-throughput drug screening. Using a fully automated organoid screening pipeline, they conduct a drug repurposing screen including 1,172 drugs. The in vivo validated hits include emetine and ouabain, small molecules approved for non-cancer indications. Functional studies demonstrated that both compounds kill PDAC cells by interfering with their ability to respond to hypoxia.