Developing Patient-derived Organoids to Predict PARP Inhibitor Response and Explore Resistance Overcoming Strategies in Ovarian Cancer

With the common use of poly ADP-ribose polymerase inhibitors (PARPi) for the man-agement of epithelial ovarian cancer (EOC) across the treatment life cycle, there is a critical need for the development of functional tests, as a complementary to genomic assays, in the study of PARPi sensitivity and resistance. Patient-derived organoids (PDOs) are found feasible for rapid functional testing and predicting drug response. Here, we established a series of PDOs from EOC and tested the sensitivity of seven cases to various agents including PARPi. PDOs recapitulated patient clinical response to platinum chemotherapy and displayed drug response heterogeneity to targeted agents including PARPi. Of three PDOs harboring mutational signature of homologous recombination repair (HRR) deficiency, two were PARPi sensitive while one was inherent resistant. Another PDO derived from a patient who relapsed during olaparib maintenance therapy was found acquired resistant to PARPi. Subsequent functional analysis revealed the potential resistant mechanisms related to replication fork protection and HRR functional restoration, and combination strategies targeting the mechanisms could reverse the resistance. Our research demonstrated the capacity of EOC PDOs for evaluating the sensitivity to PARPi under different settings, exploring mechanisms of resistance, and identifying effective combined strategies, which has implications for the clinical application of PARPi.