The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors

Helei Hou,Dantong Sun,Xiaochun Zhang

doi:10.1186/s12935-019-0937-4

Abstract

The MDM2 protein encoded by the mouse double minute 2 (MDM2) gene is the primary negative regulatory factor of the p53 protein. MDM2 can ligate the p53 protein via its E3 ubiquitin ligase, and the ubiquitinated p53 can be transferred to the cytoplasm and degraded by proteasomes. Therefore, MDM2 can maintain the stability of p53 signaling pathway. MDM2 amplification has been detected in many human malignancies, including lung cancer, colon cancer and other malignancies. MDM2 overexpression is associated with chemotherapeutic resistance in human malignancies. The mechanisms of chemotherapeutic resistance by MDM2 overexpression mainly include the p53–MDM2 loop-dependent and p53–MDM2 loop-independent pathways. But the role of MDM2 overexpression in tyrosine kinase inhibitors resistance remains to be further study. This paper reviews the possible mechanisms of therapeutic resistance of malignancies induced by MDM2 amplification and overexpression, including chemotherapy, radiotherapy, targeted agents and hyperprogressive disease of immunotherapy. Besides, MDM2-targeted therapy may be a potential new strategy for treating advanced malignancies.

Highlights

Other protein molecules, such as homeobox A13 (HOXA13), play important roles in fluorouracil (5-FU) resistance in tumor cells by regulating the mouse double minute 2 (MDM2)–p53 loop [23]
In addition to secondary drug resistance caused by heterogeneity of malignancies [4], primary drug resistance limits the tyrosine kinase inhibitor (TKI) treatment of malignancies [5]
Cisplatin Cisplatin, doxorubicin, gemcitabine, 5-FU, radiotherapy Temozolomide Chemotherapy, target therapy TKIs TKIs TKIs Immunotherapy Immunotherapy binding of mouse double minute 2 (MDM2) and p53 by competitive binding to the region I of MDM2 protein, resulting in the increasing of p53 level and activation of p53 signaling pathway [52, 53]

Summary

Introduction

Other protein molecules, such as homeobox A13 (HOXA13), play important roles in fluorouracil (5-FU) resistance in tumor cells by regulating the MDM2–p53 loop [23]. Adenovirusmediated p53 gene therapy can inhibit the binding of p53 and MDM2, which reduces p53 degradation and enhances tumor cells’ sensitivity to radiotherapy, especially tumor cells with MDM2 overexpression [25].

Results

Conclusion