The interference of IRF-1 and PKR in the antitumoral action of MDM2 inhibitors

Abstract

The development of new drugs for cancer treatment has been based on the mechanisms of action knowledge of tumor suppressor genes or oncogenes, called target-specific drugs. MDM2 inhibitors are promising drugs for the treatment of patients with wild-type alleles and normal expression of TP53. MDM2 and MDMx are two proteins considered as bona-fide oncogenes that participate on the ubiquitination and, therefore, on p53 degradation. In patients with tumor, that have p53 wild-type alleles, these two proteins are often increased, leading to increased degradation of p53. MDM2 inhibitors lead to the restoration of p53 levels and consequent cell cycle arrest and apoptosis, induced by DNA damage. Some of these drugs are already in clinical trials. IRF-1 and PKR are proteins of the Interferon system and also influence the process of cell cycle arrest due to DNA damage and apoptosis induction. While IRF-1 exerts this function independently of p53, the PKR expression is modulated by p53 and contributes at least in part, to the p53 tumor suppressor activity. In this project, we intend to use cells deficient for IRF-1 or PKR and evaluate the action of MDM2 inhibitors. Our hypothesis is that, in cells deficient for IRF-1, the activity of MDM2 inhibitors will be reduced, since the restoration of p53 activity would not compensate the IRF-1 absence. In the same way, in cells without PKR, the p53 activity would be partially restored since the PKR-dependent pathways would remain defective. In practice, understanding the role of IRF-1 and PKR may contribute to a better selection of patients treated with MDM2 inhibitors. (AU)