دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label treatment.
المؤلفون: Hirt CK; Institute of Molecular Health Sciences, ETH Zurich, Switzerland.; Institute of Pharmacology and Toxicology, University Zurich, Switzerland., Booij TH; NEXUS Personalized Health Technologies, ETH Zurich, Switzerland., Grob L; NEXUS Personalized Health Technologies, ETH Zurich, Switzerland.; SIB Swiss Institute of Bioinformatics, Zurich, Switzerland., Simmler P; Institute of Molecular Health Sciences, ETH Zurich, Switzerland.; Institute of Pharmacology and Toxicology, University Zurich, Switzerland., Toussaint NC; NEXUS Personalized Health Technologies, ETH Zurich, Switzerland.; SIB Swiss Institute of Bioinformatics, Zurich, Switzerland., Keller D; NEXUS Personalized Health Technologies, ETH Zurich, Switzerland., Taube D; Institute of Molecular Health Sciences, ETH Zurich, Switzerland., Ludwig V; Institute of Molecular Health Sciences, ETH Zurich, Switzerland., Goryachkin A; Institute of Molecular Health Sciences, ETH Zurich, Switzerland., Pauli C; Department of Pathology and Molecular Pathology, University Hospital Zurich, Switzerland., Lenggenhager D; Department of Pathology and Molecular Pathology, University Hospital Zurich, Switzerland., Stekhoven DJ; NEXUS Personalized Health Technologies, ETH Zurich, Switzerland.; SIB Swiss Institute of Bioinformatics, Zurich, Switzerland., Stirnimann CU; NEXUS Personalized Health Technologies, ETH Zurich, Switzerland., Endhardt K; Department of Pathology and Molecular Pathology, University Hospital Zurich, Switzerland., Ringnalda F; Institute of Molecular Health Sciences, ETH Zurich, Switzerland., Villiger L; Institute of Molecular Health Sciences, ETH Zurich, Switzerland.; Institute of Pharmacology and Toxicology, University Zurich, Switzerland., Siebenhüner A; Comprehensive Cancer Center, University Hospital Zurich, Switzerland., Karkampouna S; Department for BioMedical Research, Urology Research laboratory, University Bern, Switzerland.; Department of Urology, Inselspital, Bern University Hospital, Switzerland., De Menna M; Department for BioMedical Research, Urology Research laboratory, University Bern, Switzerland.; Department of Urology, Inselspital, Bern University Hospital, Switzerland., Beshay J; Discovery Services, Oncotest, Charles River, Freiburg, Germany., Klett H; Discovery Services, Oncotest, Charles River, Freiburg, Germany., Kruithof-de Julio M; Department for BioMedical Research, Urology Research laboratory, University Bern, Switzerland.; Department of Urology, Inselspital, Bern University Hospital, Switzerland., Schüler J; Discovery Services, Oncotest, Charles River, Freiburg, Germany., Schwank G; Institute of Molecular Health Sciences, ETH Zurich, Switzerland.; Institute of Pharmacology and Toxicology, University Zurich, Switzerland.
المصدر: Cell genomics [Cell Genom] 2022 Feb; Vol. 2 (2), pp. 100095.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier, Inc Country of Publication: United States NLM ID: 9918284260106676 Publication Model: Print Cited Medium: Internet ISSN: 2666-979X (Electronic) Linking ISSN: 2666979X NLM ISO Abbreviation: Cell Genom Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: [New York] : Elsevier, Inc., [2021]-
مستخلص: 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.
Competing Interests: Declaration of interests Janette Beshay, Hagen Klett and Julia Schueler are employees of Charles River Research Services Germany GmbH. The other authors declare no competing interests.
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معلومات مُعتمدة: 160230 Switzerland SNSF_ Swiss National Science Foundation
فهرسة مساهمة: Keywords: ARID1A; CRISPR; Drug Screening; HIF-1α; Organoids; PDX - BRCA2; Pancreatic Cancer
تواريخ الأحداث: Date Created: 20220221 Latest Revision: 20220225
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC7612395
DOI: 10.1016/j.xgen.2022.100095
PMID: 35187519
قاعدة البيانات: MEDLINE
الوصف
تدمد:2666-979X
DOI:10.1016/j.xgen.2022.100095