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Review Article | Open Access

Targeting the MYCN-MDM2 pathways for cancer therapy: Are they druggable?

Wei Wanga,b( ), Yi Dua, Sayantap Dattaa, Josef F. Fowlera, Hannah T. Sanga, Najah Albadaric, Wei Lic, Jennifer Fosterd, Ruiwen Zhanga,b( )
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
Drug Discovery Institute, University of Houston, Houston, TX 77204, USA
College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
Texas Children’s Hospital, Department of Pediatrics, Section of Hematology-Oncology Baylor College of Medicine, Houston, TX 77030, USA

Peer review under the responsibility of the Genes & Diseases Editorial Office, in alliance with the Association of Chinese Americans in Cancer Research (ACACR, Baltimore, MD, USA).

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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.

Keywords

MDM2MYCNNeuroblastomaSignaling pathwayTargeted therapy

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Genes & Diseases
Volume 12 Issue 2,
March 2025
Article number: 101156
DOI: 10.1016/j.gendis.2023.101156
Cite this article:
Wang W, Du Y, Datta S, et al. Targeting the MYCN-MDM2 pathways for cancer therapy: Are they druggable?. Genes & Diseases, 2025, 12(2): 101156. https://doi.org/10.1016/j.gendis.2023.101156

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Received: 15 May 2023
Revised: 11 September 2023
Accepted: 26 September 2023
Published: 27 October 2023
© 2023 The Authors.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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