Abstract A027: Enhancing cisplatin efficacy through Notch inhibition by auranofin in ovarian cancer

Abstract The Notch pathway regulates cell proliferation, differentiation, and stem cell maintenance. Aberrant Notch activation plays a critical role in cancer initiation, progression, and chemoresistance. Mutations and amplifications in Notch pathway genes are frequently observed in high-grade serous ovarian cancers and are associated with poor clinical outcomes. Among the four Notch receptors, Notch3 alterations show the strongest correlation with poor overall survival. Previously, we identified auranofin, an oral gold compound, as a novel Notch pathway inhibitor that disrupts DNA binding by RBPJ, the key downstream transcriptional effector of the pathway. Here, we evaluated the response of eight ovarian cancer cell lines to auranofin and found IC50 values ranging from 1.7 to 12 µM, with Notch3-negative SKOV3 cells exhibiting the highest IC50. In Notch-dependent OVCAR3 cells, auranofin synergized with cisplatin to enhance cell killing, whereas it demonstrated antagonism in SKOV3 cells. Importantly, auranofin treatment resulted in a dose-dependent reduction of RBPJ occupancy at the Notch target promoters HES1 and HES4, supporting its role as a Notch inhibitor. Strikingly, auranofin also enhanced cisplatin efficacy in an OVCAR3-derived xenograft model. Furthermore, in eight patient-derived ovarian cancer organoid models, auranofin improved cisplatin response in organoids from platinum-sensitive patients and restored cisplatin sensitivity in a subset of platinum-resistant models. These findings underscore the therapeutic potential of auranofin to improve platinum-based treatment in Notch3-expressing ovarian cancers. Citation Format: Hua-Ying Fan, Robert J. Lake, Parisa Nikeghbal, Irina V . Lagutina, Kimberly K. Leslie, Mara P. Steinkamp. Enhancing cisplatin efficacy through Notch inhibition by auranofin in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A027.