Targeting the MDM2–p53 interaction as a therapeutic strategy for the treatment of cancer

Susan K Peirce, Harry W Findley

Department of Pediatrics, Division of Hematology and Oncology Emory University School of Medicine, Aflac Cancer Center and Blood Service, Atlanta, Georgia, USA

Abstract: The tumor suppressor p53 functions as an important defense against the development of cancer, and is negatively regulated by interaction with the oncogene and E3 ligase MDM2. In a tightly controlled system of feedback, MDM2 is, in turn, inhibited by the tumor suppressor p14^ARF. The inhibition of MDM2-p53 interaction is an appealing therapeutic strategy for the treatment of cancer, and significant advances have been made in the development of small-molecule inhibitors which block this interaction and reactivate wild-type p53. However, the p53 gene is frequently mutated or deleted in cancer, or the wild-type p53 function inhibited by high levels of MDM2. Neuroblastoma (NB) is one such cancer and has presented a major therapeutic challenge in pediatric oncology. Although most NB tumors have wild-type p53, the p14^ARF/MDM2/p53 pathway is often altered, leading to resistance to many mainstay chemotherapeutics and a high incidence of relapse. In preclinical studies, the MDM2/p53 interaction inhibitor nutlin-3a has shown effectiveness in the treatment of chemoresistant NB with wild-type, mutant or null-p53 status, indicating that nutlin-3a has potential for the treatment of a broad range of chemoresistant and relapse tumors.

Keywords: p53, MDM2, MDMX, TAp73, nutlin-3a