Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death

Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth leading cause of cancer death in the western world, with a 5-year survival rate below 5%. Murine double minute 2 (Mdm2) is an important negative regulator of the tumor suppressor p53. Reactivation of wild-type p53 is a promising treatment strategy, and inhibitors of Mdm2 have already entered clinical trials. To investigate the effects of Mdm2 inhibitors in PDAC, we used a murine cell line platform with a genetically defined status of p53. Here, we describe that Mdm2 inhibitors can act on a subset of murine PDAC cell lines p53 independently. Furthermore, we observed that Mdm2 inhibitors increase the sensitivity of murine PDAC cell lines toward topoisomerase II inhibitors by inducing effector caspase-independent cell death. The combination of Mdm2 inhibitors with topoisomerase II inhibitors acts independent of the survival factor NFκB/RelA. Mechanistically, Mdm2 inhibitors increase topoisomerase II inhibitor-induced DNA double-strand breaks. We show that Mdm2 binds to Nbs1 of the Mre11-Rad50-Nijmegen breakage syndrome (Nbs) 1 DNA repair complex. In addition, we provide evidence that Mdm2 inhibitors delay DNA repair. These findings may help to design novel therapeutic strategies to overcome therapeutic resistance of PDAC. What's new? Using a murine pancreatic cancer cell line platform with genetically defined p53 status, the authors demonstrate that inhibitors of Mdm2, a negative regulator of the tumor suppressor p53, increases the sensitivity of pancreatic cancer cells towards topoisomerase II inhibitors in a p53-independent manner. They provide evidence that Mdm2 binds to Nijmegen breakage syndrome (Nbs) 1 of the Mre11-Rad50-Nbs1 DNA double strand break repair complex, thus providing evidence that Mdm2 inhibitors may be therapeutically effective by delaying repair of DNA double strand breaks in a subset of pancreatic cancer cells. Copyright © 2012 UICC.