Elsesy, Mohamed E, Oh-Hohenhorst, Su Jung, Oing, Christoph, Eckhardt, Alicia, Burdak-Rothkamm, Susanne 
ORCID: 0000-0002-3840-2844, Alawi, Malik, Mueller, Christian, Schueller, Ulrich, Maurer, Tobias, von Amsberg, Gunhild et al (show 3 more authors)
(2023)
Preclinical patient-derived modeling of castration-resistant prostate cancer facilitates individualized assessment of homologous recombination repair deficient disease.
MOLECULAR ONCOLOGY, 17 (6).
pp. 1129-1147.
Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | castration-resistant prostate cancer, ex vivo tumor cultures, homologous recombination, PARP inhibition, patient-derived organoids |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 02 Feb 2024 10:30 |
| Last Modified: | 02 Feb 2024 10:30 |
| DOI: | 10.1002/1878-0261.13382 |
| Open Access URL: | https://doi.org/10.1002/1878-0261.13382 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3178289 |
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