LAUSR

Introduction: As opposed to other malignancies, the majority of endometrial cancer (EC) cases are wild-type for TP53. Approximately 15% of TP53-mutated EC have heterozygous mutation, preserving a fraction of wild-type signaling. Given the demonstrated impact of p53 signaling on radiotherapy (RT) response in EC, we explored the role of MDM2 inhibition as a novel radio-sensitizing strategy for EC. Methods: To assess the impact of MDM2 inhibition on cell viability and radiation response, we employed 3 parental EC cell lines of differing TP53 status (JHUEM2, Hec108, Hec1B), as well as monoclonal isolates of JHUEM2 after TP53 knockout. An intron-targeting approach facilitated TP53 cDNA complementation. Radiation response was determined by assessing cell viability with CellTiter-Glo and calculating area under the curve (AUC) with multiple dose points. Nutlin-3 and AMG-232 were both tested. All experiments were carried out in triplicate. Highest Single Agent (HSA) analysis was used to determine additive versus synergistic effects. Results: Nutlin-3 and AMG-232 were both observed to have a negative impact on cell viability, dependent on TP53 context. In the wild-type TP53 cell line (JHUEM2), IC50s for Nutlin-3 and AMG-232 were observed to be 1.417 and 0.218 μM, respectively. The heterozygous TP53-mutated cell line, Hec108, had corresponding IC50s of 6.04 and 1.10 μM. The Hec1B cell line did not exhibit a response to either drug. Subsequently, IC50 curves were calculated in the presence of multiple dose points of gamma irradiation administered as one fraction. A synergistic effect was observed with Nutlin-3 and AMG-232 in JHUEM2, while only AMG-232 reached synergy in Hec108. Conclusions: Overall, these findings nominate MDM2 inhibitors as potential radio-sensitizing strategies that would be applicable to a large proportion of EC. Given the lack of benefit from cisplatin-based radio-sensitization for recurrent EC in a recent clinical trial, this provides a novel biomarker driven strategy. Citation Format: Aaron Petty, Brian Yard, Arda Durmaz, Jacob Scott, Roberto Vargas. MDM2 inhibition as a novel radio-sensitizing strategy for endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1091.