1 research outputs found
Preclinical patientâderived modeling of castrationâresistant prostate cancer facilitates individualized assessment of homologous recombination repair deficient disease
The use of mutation analysis of homologous recombination repair (HRR) genes to estimate PARPâinhibition response may miss a larger proportion of responding patients. Here, we provide preclinical models for castrationâresistant prostate cancer (CRPC) that can be used to functionally predict HRR defects. Inâvitro, CRPC LNCaP sublines revealed an HRR defect and enhanced sensitivity to olaparib and cisplatin due to impaired RAD51 expression and recruitment. Exâvivoâinduced castrationâresistant tumor slice cultures or tumor slice cultures derived directly from CRPC patients showed increased olaparibâ or cisplatinâassociated enhancement of residual radiationâinduced ÎłH2AX/53BP1 foci. We established patientâderived 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 patientâderived 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