Inhibition of Mdm2-p53 interaction as a therapeutic strategy for the treatment of p53 wild-type rhabdomyosarcoma

Abstract

Targeting MDM2-p53 interaction to enhance p53 activity represents a potentially attractive antitumoral approach for p53 wild-type tumors. However, results from early-phase clinical trials in hematological and solid cancers have shown limited efficacy of MDM2 inhibitors, underscoring the need to explore more effective combinations with other 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 (p53 WT RMS). Cell survival, cell death, and apoptosis analysis revealed synergistic effects of combining siremadlin + olaparib in vitro. The combination of both drugs led to a significant increase in p53 activity, as evidenced by p53 accumulation and K382 acetylation, along with an increased expression of p53 targets. Furthermore, treatment with both drugs resulted in significant reduction of tumor growth and increased overall survival when compared to individual treatments and control. Overall, our study demonstrates, for the first time, the synergistic effect of combining siremadlin + olaparib in inhibiting p53 WT RMS tumor growth in vitro and in vivo. Our findings support the potential to study the combination of both drugs in clinical trials and warrants further investigation in other tumors with similar molecular features.

Date of Award	22 Nov 2024
Original language	English
Supervisor	Josep Roma Castanyer (Director) & Lucas Moreno Martin Retortillo (Director)