MDM2 in Tumor Biology and Cancer Therapy: A Review of Current Clinical Trials

The Murine Double Minute 2 (<i>MDM2</i>) gene encodes an E3 ubiquitin ligase that negatively regulates the tumor suppressor p53, maintaining low p53 levels through ubiquitination and proteasomal degradation. MDM2 overexpression in various malignancies leads to reduced p53 activity, contributing to tumor initiation and resistance to therapies. As such, MDM2 is a promising target for drug development. Innovative small-molecule inhibitors are being designed to disrupt the MDM2-p53 interaction, thereby restoring p53's tumor-suppressive functions. This review focuses on clinical trials evaluating MDM2 inhibition for cancer therapy. MDM2 exerts its oncogenic effects primarily through its interaction with p53 but also has p53-independent functions involved in cell cycle progression and DNA repair. Elevated MDM2 expression is associated with poor prognosis across various cancers, including dedifferentiated liposarcoma, breast cancer, and glioblastoma. Targeting MDM2 with inhibitors has shown promising potential in clinical development, aiming to reactivate p53's functions in tumors with wild-type TP53, improving therapeutic outcomes in cancer treatment.