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

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.