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

Hirt, Christian K; Booij, Tijmen H; Grob, Linda; Simmler, Patrik; Toussaint, Nora C; Keller, David; Taube, Doreen; Ludwig, Vanessa; Goryachkin, Alexander; Pauli, Chantal; Lenggenhager, Daniela; Stekhoven, Daniel J; Stirnimann, Christian U; Endhardt, Katharina; Ringnalda, Femke; Villiger, Lukas; Siebenhüner, Alexander; Karkampouna, Sofia; De Menna, Marta; Beshay, Janette; ... (2022). Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label treatment. Cell genomics, 2(2), p. 100095. Elsevier 10.1016/j.xgen.2022.100095

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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 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 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 and identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Urology

UniBE Contributor:

Karkampouna, Sofia; De Menna, Marta and Kruithof-de Julio, Marianna

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2666-979X

Publisher:

Elsevier

Language:

English

Submitter:

Pubmed Import

Date Deposited:

22 Feb 2022 10:22

Last Modified:

22 Feb 2022 10:29

Publisher DOI:

10.1016/j.xgen.2022.100095

PubMed ID:

35187519

Uncontrolled Keywords:

ARID1A CRISPR Drug Screening HIF-1α Organoids PDX - BRCA2 Pancreatic Cancer

BORIS DOI:

10.48350/165885

URI:

https://boris.unibe.ch/id/eprint/165885

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