Abstract 5473: Combined inhibition of MDM2 and PARP lead to a synergistic anti-tumoral response in p53 wild-type rhabdomyosarcoma

Abstract

Abstract Targeting MDM2-p53 interaction to enhance p53 activity represents an attractive antitumoral strategy for p53 wild-type tumors. However, early-phase clinical trials in hematological and solid cancers have shown limited efficacy of MDM2 inhibitors highlighting the necessity for exploring more effective combinations with additional agents. In this study, we provide results from a 22-drug combination screening demonstrating the therapeutic potential of combining Siremadlin (MDM2 inhibitor) and Olaparib (PARP inhibitor) for treating p53 wild-type rhabdomyosarcoma (RMS). Cell survival, cell death and apoptosis analysis revealed synergistic effects when combining Siremadlin and Olaparib in vitro. Combination of both drugs resulted in a significant increase of p53 activity as evidenced by p53 accumulation and K382 acetylation along with an increased expression of p53 targets. Finally, combination of both drugs resulted in significant reduction of tumor growth and increased overall survival outperforming individual treatments and control groups. In summary, our study demonstrates, for the first time, the synergistic effect of the combination between Siremadlin and Olaparib in the inhibition of p53 wild-type RMS tumor growth in vitro and in vivo. These findings advocate for the exploration of this drug combination in clinical trials and underscore the need for further investigation in tumors sharing similar molecular features. Citation Format: Guillem Pons, Gabriel Gallo-Oller, Lia García-Gilabert, Patricia Zarzosa, Júlia Sansa-Girona, Natalia Navarro, Paula Cabré-Fernández, Miguel F Segura, Josep Sánchez de Toledo, Soledad Gallego, Lucas Moreno, Josep Roma. Combined inhibition of MDM2 and PARP lead to a synergistic anti-tumoral response in p53 wild-type rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5473.