Klin Onkol 2018; 31(Suppl 2): 63-70. DOI: 10.14735/amko20182S63.
Background: HDM2 and HDMX proteins are key negative regulators of the tumor suppressor p53. Under normal conditions, p53 protein expression is maintained at a low level, whereas under stress conditions, this negative regulation is alleviated to increase the p53 level. HDM2 and HDMX are overexpressed in many cancer types, mainly in tumors with wild type p53, such as sarcomas. In addition to an inactivating mutation in the TP53 gene, HDM2 and HDMX overexpression represents another kind of p53 inactivation pathway. Aim: In this review, we first briefly describe the roles of HDM2 and HDMX proteins and then the increased occurrence of their overexpression and the possible causes of this overexpression in different human cancer types as well as therapeutic approaches targeting HDM2 and HDMX for the treatment of human cancer. Conclusion: HDM2 and HDMX are important therapeutic targets. The interruption of their negative effect on p53 pathway by compounds such as nutlins, leads to the reactivation of the p53 pathway. However, a deeper understanding of HDM2-HDMX-p53 structure and function will enable the identification of new therapeutic strategies that could help to provide more specific and more efficient therapies for cancer patients. Several small molecules and peptides are the subject of clinical testing in phase I, II and even III trials.
