Targeting the MYCN-MDM2 Pathways for Cancer Therapy: Are They Druggable?

Authors

Wei Wang
Yi Du
Sayantap Datta
Josef F Fowler
Hannah T Sang
Najah Albadari
Wei Li
Jennifer Foster
Ruiwen Zhang

Publication Date

3-1-2025

Journal

Genes & Diseases

DOI

10.1016/j.gendis.2023.101156

PMID

39802403

PMCID

PMC11719324

PubMedCentral® Posted Date

10-27-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

MDM2, MYCN, Neuroblastoma, Signaling pathway, Targeted therapy

Abstract

Targeting oncogenes and their interactive partners is an effective approach to developing novel targeted therapies for cancer and other chronic diseases. We and others have long suggested the MDM2 oncogene being an excellent target for cancer therapy, based on its p53-dependent and -independent oncogenic activities in a variety of cancers. The MYC family proteins are transcription factors that also regulate diverse biological functions. Dysregulation of MYC, such as amplification of MYCN, is associated with tumorigenesis, especially for neuroblastoma. Although the general survival rate of neuroblastoma patients has significantly improved over the past few decades, high-risk neuroblastoma still presents a poor prognosis. Therefore, innovative and more potent therapeutic strategies are needed to eradicate these aggressive neoplasms. This review focuses on the oncogenic properties of MYCN and its molecular regulation and summarizes the major therapeutic strategies being developed based on preclinical findings. We also highlight the potential benefits of targeting both the MYCN and MDM2 oncogenes, providing preclinical evidence of the efficacy and safety of this approach. In conclusion, the development of effective small molecules that inhibit both MYCN and MDM2 represents a promising new strategy for the treatment of neuroblastoma and other cancers.