Nectin-4-directed therapeutic repositioning augments anti-tumor efficacy in epithelial ovarian carcinoma

Epithelial ovarian carcinoma (EOC) accounts for over 90% of ovarian cancer cases, yet the five-year survival rate remains below 35%, highlighting the urgent need for more effective therapies. Nectin-4, a single pass membrane protein involved in cell adhesion, has emerged as a promising target for treating solid tumors; however, its therapeutic potential in EOC is still under investigation. In this study, we evaluate the feasibility of repurposing a Nectin-4-targeted antibody-drug conjugate (ADC) as a treatment for Nectin-4-positive EOC, and explore combination strategies to enhance therapeutic outcomes. We demonstrate that enfortumab vedotin (EV), a clinically approved anti-Nectin-4 ADC, effectively inhibits tumor growth in Nectin-4-positive EOC models both in vitro and in vivo. Additionally, we identify acetalax, a previously approved laxative, as having efficacy against Nectin-4-positive EOC tumors. Notably, combining EV with acetalax synergistically induces tumor cell death in vitro and significantly reduces tumor relapse in vivo. Mechanistically, through RNA sequencing, reverse phase protein array, and mass spectrometry-based lipid profiling, we reveal that both EV and acetalax treatments disrupt fatty acid metabolism pathways in EOC cells, which may underpin their tumor-suppressive effects. These findings support the potential of Nectin-4-directed ADCs as a promising therapeutic approach for EOC, with combination therapy involving acetalax offering enhanced efficacy and warranting further clinical investigation.