Therapeutic Effects of Lurbinectedin in PARP Inhibitor-Resistant High-Grade Serous Ovarian Cancer Using Patient-Derived Cell Lines and Organoid Models.

High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy which is often treated with platinum-based chemotherapy and PARP inhibitors (PARPi). However, PARPi resistance remains a major clinical challenge, necessitating alternative therapeutic strategies. In this study, we establish the first known patient-derived organoid models directly from PARPi-resistant HGSOC and demonstrate that they preserve the original tumor architecture and key biomarkers (EpCAM, CA125, PAX8, HER2, MEK1/2, Cyclin E1), thus providing unique preclinical models for drug testing. These organoids were used to evaluate lurbinectedin in comparison with standard carboplatin and paclitaxel. While lurbinectedin showed comparable apoptotic effects to paclitaxel and superior activity to carboplatin, it induced chromosomal breaks to different extents in different cell lines, suggesting a distinct mechanism of action. Importantly, this work does not advocate for lurbinectedin as a superior therapy but, rather, demonstrates the utility of organoid models in uncovering drug-specific genomic effects. Our findings underscore the critical need for expanded testing using clinically relevant models to identify more effective strategies against PARPi-resistant disease.