Auranofin potentiates cisplatin response in the setting of context-dependent NOTCH-associated signaling states in endometrial cancer

Abstract Therapeutic resistance remains a major challenge in advanced and recurrent endometrial cancer (EC). Aberrant NOTCH signaling has been associated with aggressive tumor behavior and therapeutic resistance across multiple malignancies, yet its therapeutic significance in EC remains incompletely defined. We investigated whether auranofin (AuR), a pleiotropic gold-containing compound that inhibits thioredoxin reductase and can disrupt RBPJ chromatin occupancy, alters platinum responsiveness in EC models. Upper-quartile NOTCH3 copy number was associated with poorer overall survival in the TCGA-UCEC cohort, although this association was not retained with median-based stratification, continuous Cox proportional-hazards modeling, or multivariable adjustment for clinicopathologic and molecular context. AuR treatment reduced RBPJ occupancy at canonical NOTCH target loci, including HES1 and HES4, across multiple EC models, although this was not accompanied by significant changes in steady-state HES1 or HES4 transcript levels in AN3CA or ARK-1 cells. Stable NOTCH3 depletion produced context-dependent effects on AuR responsiveness and significantly enhanced cisplatin (CDDP) sensitivity in AN3CA cells. Pharmacologic AuR treatment similarly potentiated CDDP response in AN3CA cells and xenografts, resulting in reduced tumor burden and prolonged endpoint-free survival following combination treatment. In contrast, ARK-1 xenografts demonstrated limited additional benefit from combined AuR plus CDDP therapy despite detectable suppression of RBPJ occupancy. Together, these findings identify context-dependent NOTCH-associated therapeutic vulnerabilities in EC and support further investigation of AuR-based platinum-sensitization strategies in biologically defined tumor contexts.