Auranofin potentiates cisplatin response through context-dependent NOTCH-associated signaling states in endometrial cancer

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 noncanonical modulator of NOTCH signaling through the transcriptional effector RBPJ, alters platinum responsiveness in EC models. Elevated NOTCH3 copy-number was associated with poorer overall survival in the TCGA-UCEC cohort. AuR treatment reduced RBPJ occupancy at canonical NOTCH target loci, including HES1 and HES4, across multiple EC models. Stable NOTCH3 depletion altered AuR responsiveness in a context-dependent manner while significantly enhancing cisplatin (CDDP) sensitivity in AN3CA cells. Pharmacologic AuR treatment similarly potentiated CDDP response in AN3CA cells and AN3CA 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 development of biomarker-guided AuR-based platinum-sensitization strategies. Statement of significanceAuranofin suppresses RBPJ-associated transcriptional activity and enhances cisplatin response in biologically distinct subsets of endometrial cancer.