Targeting phospholipase D1 overcomes platinum resistance and enhances cisplatin efficacy in ovarian cancer

Background: Platinum-based chemotherapy is the standard treatment for high-grade serous ovarian cancer (HGSOC), yet the development of platinum resistance remains a major barrier to effective therapy. Phospholipase D1 (PLD1) has been implicated in tumor progression and stress response pathways, but its potential as a therapeutic target in platinum-resistant ovarian cancer (OC) has not been clearly defined. This study investigated whether targeting PLD1 can restore platinum sensitivity and improve therapeutic efficacy in resistant disease. Methods: The impact of PLD1 inhibition was evaluated using OC cell lines, patient-derived primary tumor cells, and both cell line-derived and patient-derived xenograft models. Functional assays measured clonogenic survival, proliferation, invasion, sphere formation, apoptosis, and DNA damage. Cisplatin responsiveness was assessed following genetic PLD1 knockdown or treatment with a PLD1 inhibitor. Results: PLD1 suppression significantly reduced survival, proliferation, and invasiveness in platinum-resistant OC cells, while inducing apoptosis and accumulation of DNA damage. Importantly, PLD1 inhibition restored cisplatin sensitivity across multiple resistant models, leading to a marked reduction in clonogenic survival. In vivo, combined PLD1 inhibition and cisplatin treatment markedly suppressed tumor growth, prolonged survival, and reduced metastatic burden in xenograft and PDX models, with greater therapeutic benefit observed in platinum-resistant tumors. Conclusions: PLD1 is a key survival determinant in platinum-resistant OC and contributes directly to treatment failure. Targeting PLD1 enhances the antitumor efficacy of cisplatin and provides strong preclinical rationale for PLD1-directed combination therapy in refractory HGSOC.