Restoring p53 Function In Sarcomas Using MDM2 Inhibitors

Abstract

MDM2 is an E3 ubiquitin ligase and the principal negative regulator of the tumor suppressor gene TP53, maintaining cellular homeostasis through a tightly controlled feedback loop in which p53 transcriptionally activates MDM2, and MDM2, in turn, ubiquitinates p53 for degradation. In several sarcomas—particularly well‑differentiated and dedifferentiated liposarcomas—MDM2 amplification at chromosome 12q15 suppresses p53 activity despite retention of a wild‑type TP53 gene. This makes the p53‑binding pocket of MDM2 an attractive therapeutic target in these tumors.

Over the past two decades, nine small‑molecule MDM2 inhibitors have entered clinical trials, including RG7112, idasanutlin, SAR405838, HDM201, APG‑115, navtemadlin, AMG‑232, milademetan, and BI‑907828, with seven advancing to later‑stage evaluation. Although none have yet received regulatory approval, early‑phase studies have demonstrated pharmacodynamic proof‑of‑concept, evidenced by p53 stabilization, induction of downstream targets such as p21, and tumor growth arrest in MDM2‑amplified models and patients.

This study compares the effectiveness of these inhibitors in the context of MDM2‑amplified sarcomas, where excessive MDM2 expression suppresses wild‑type TP53 activity. Pharmacologic blockade of the p53–MDM2 interaction can release p53 from inhibition, thereby restoring its tumor‑suppressive functions and inducing cell‑cycle arrest or apoptosis in cancer cells.