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Lookup NU author(s): Dr Christoph OingORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. The use of mutation analysis of homologous recombination repair (HRR) genes to estimate PARP-inhibition response may miss a larger proportion of responding patients. Here, we provide preclinical models for castration-resistant prostate cancer (CRPC) that can be used to functionally predict HRR defects. In vitro, CRPC LNCaP sublines revealed an HRR defect and enhanced sensitivity to olaparib and cisplatin due to impaired RAD51 expression and recruitment. Ex vivo-induced castration-resistant tumor slice cultures or tumor slice cultures derived directly from CRPC patients showed increased olaparib- or cisplatin-associated enhancement of residual radiation-induced γH2AX/53BP1 foci. We established patient-derived tumor organoids (PDOs) from CRPC patients. These PDOs are morphologically similar to their primary tumors and genetically clustered with prostate cancer but not with normal prostate or other tumor entities. Using these PDOs, we functionally confirmed the enhanced sensitivity of CRPC patients to olaparib and cisplatin. Moreover, olaparib but not cisplatin significantly decreased the migration rate in CRPC cells. Collectively, we present robust patient-derived preclinical models for CRPC that recapitulate the features of their primary tumors and enable individualized drug screening, allowing translation of treatment sensitivities into tailored clinical therapy recommendations.
Author(s): Elsesy ME, Oh-Hohenhorst SJ, Oing C, Eckhardt A, Burdak-Rothkamm S, Alawi M, Muller C, Schuller U, Maurer T, von Amsberg G, Petersen C, Rothkamm K, Mansour WY
Publication type: Article
Publication status: Published
Journal: Molecular Oncology
Year: 2023
Volume: 17
Issue: 6
Pages: 1129-1147
Print publication date: 01/06/2023
Online publication date: 24/01/2023
Acceptance date: 23/01/2023
Date deposited: 26/07/2024
ISSN (print): 1574-7891
ISSN (electronic): 1878-0261
Publisher: John Wiley and Sons Ltd
URL: https://doi.org/10.1002/1878-0261.13382
DOI: 10.1002/1878-0261.13382
Data Access Statement: Sequence data have been deposited in the European Nucleotide Archive (ENA) at EMBL-EBI under accession number PRJEB55017 (https://www.ebi.ac.uk/ena/browser/view/PRJEB55017). Generated raw data supporting the findings of this study are available from the corresponding author (WM) on request.
PubMed id: 36694344
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