Preclinical patient-derived modeling of castration-resistant prostate cancer facilitates individualized assessment of homologous recombination repair deficient disease.
PARP inhibition
castration-resistant prostate cancer
ex vivo tumor cultures
homologous recombination
patient-derived organoids
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
Jun 2023
Jun 2023
Historique:
revised:
24
10
2022
received:
10
08
2022
accepted:
23
01
2023
medline:
12
6
2023
pubmed:
26
1
2023
entrez:
25
1
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36694344
doi: 10.1002/1878-0261.13382
pmc: PMC10257417
doi:
Substances chimiques
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1129-1147Subventions
Organisme : Bundesministerium für Bildung und Forschung
ID : 02NUK032
Organisme : Bundesministerium für Bildung und Forschung
ID : 02NUK035B
Organisme : Deutscher Akademischer Austausch Dienst Kairo
Organisme : Mildred-Scheel Nachwuchszentrum, HATRIC4, Hamburg
Informations de copyright
© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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