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

Pancreatic cancer (PDAC) is a highly aggressive malignancy with poor response to chemotherapy. The identification of novel therapies is therefore urgently needed. Here we establish a human PDAC organoid biobank and apply CRISPR-Cas9 genome editing and drug screening to systematically study drug-gene interactions and to identify compounds effectively inhibiting PDAC growth. We find that missense- but not frameshift mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib and VE-821. In an automated drug-repurposing screen with >1000 FDA-approved compounds we furthermore identified several drugs that effectively kill PDAC organoids. Within the in vivo validated hits are emetine and ouabain, compounds which are approved for non-cancer indications and which perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology via genome editing and drug screening in tumor organoid biobanks.