Abstract 6799: The interaction of notch signaling and P53 reactivation in endometrial and ovarian cancer therapy
Authors: Daisy Belmares-Ortega, Lane E. Smith, Jamie L. Padilla, Geneva L. Williams, Robert J. Lake, Hua-Ying Fan, Kimberly K. Leslie
Journal: Cancer Research (2025)

Abstract Across all cancer sites, uterine and uterine cervix cancers have worsened in survival outcomes within the last few decades. Among cancers of the female reproductive organs, endometrial cancer remains the most commonly diagnosed malignancy and is now the most lethal. Deaths from endometrial cancer surpassed those from ovarian cancer just this year. The most aggressive endometrial cancers, serous adenocarcinomas, arise from mutations in p53, leading to loss of the tumor suppressive functions of wild type p53. Endometrial serous adenocarcinomas and ovarian cancers are both associated with an increased recurrence risk. Another aberrant pathway involved in endometrial cancer cell proliferation is Notch signaling, which is hyperactive in the most aggressive endometrial and ovarian cancers. MicroRNA (miRNA) expression profiles have been studied and reveal a signaling protein, NOTCH2 is a likely target related to recurrence. To study the relationship between p53 mutations and Notch signaling, endometrial adenocarcinoma and recurrent ovarian cancer cell lines including KLE, AN3CA, and PEO4 were employed for these studies due to their overexpression of Notch signaling (AN3CA), mutated p53 status (KLE, AN3CA, and PEO4), and as a cancerous recurrence model (PEO4). The curcumin-analogue AKT-100 was utilized as a mutant p53 reactivator agent in our studies to recreate the wild type p53 pro-apoptotic transcriptome. Additionally, our studies included a key down-regulator of the Notch-signaling pathway, auranofin. Auranofin as a Notch inhibitor can be used to prevent recurrence. While AKT-100 and auranofin were active in both cell lines as single agents, KLE cells were less sensitive to Auranofin due to low Notch signaling at baseline compared to AN3CA cells with high baseline activation of Notch. Interestingly, single agent AKT-100 treatment of KLE cells resulted in enhancement of the Notch signaling pathway as a resistance mechanism. This finding set the stage for the dual treatment of KLE cells with AKT-100 and Auranofin to prevent Notch upregulation. The combination of AKT-100 and Auranofin was highly synergistic (Combinatorial Index = 0.25). To confirm the mechanism of drug synergy, RNA sequencing, target protein expression and chromatin immunoprecipitation studies will be employed to confirm the effect of each agent on p53 and Notch signaling. These studies identify a novel combinatorial drug regimen tailored for the treatment of the most aggressive endometrial and ovarian cancers and identify an important mechanism underlying drug synergy. Citation Format: Daisy Belmares-Ortega, Lane E. Smith, Jamie L. Padilla, Geneva L. Williams, Robert J. Lake, Hua-Ying Fan, Kimberly K. Leslie. The interaction of notch signaling and P53 reactivation in endometrial and ovarian cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6799.