Journal
PHARMACOLOGICAL RESEARCH
Volume 179, Issue -, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2022.106232
Keywords
Ovarian cancer; Patient derived organoid; PARP inhibitor; Functional test; Resistant mechanism; Combination therapy
Categories
Funding
- National Key Research and Development of China [2021YFF0502400]
- Innovative research team of high-level local universities in Shanghai [22137006 82073713 82104033, U2106227]
- National Natural Science Foundation of China
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This study establishes patient-derived organoids (PDOs) from epithelial ovarian cancer (EOC) and evaluates their sensitivity to poly ADP-ribose polymerase inhibitors (PARPi). The PDOs recapitulate patient clinical response and demonstrate heterogeneity in drug response. The study also reveals potential mechanisms of resistance and identifies combination strategies to reverse resistance.
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 estab-lished 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 heteroge-neity 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 resis-tance. 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.
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