The MDM2/MDMX-p53 Antagonist PM2 Radiosensitizes Wild-Type p53 Tumors.

Abstract

Radiotherapy amplifies p53 expression in cancer cells with wild-type (wt) p53. Blocking the negative regulators MDM2 and MDMX stabilizes p53 and may therefore potentiate radiotherapy outcomes. In this study, we investigate the efficacy of the novel anti-MDM2/X stapled peptide PM2 alone and in combination with external gamma radiation <i>in vitro</i> and <i>in vivo</i> PM2 therapy combined with radiotherapy elicited synergistic therapeutic effects compared with monotherapy in cells with wt p53 in both <i>in vitro</i> and <i>in vivo</i> assays, whereas these effects did not manifest in p53 ^-/- cells. Biodistribution and autoradiography of ¹²⁵I-PM2 revealed high and retained uptake homogenously distributed throughout the tumor. In mice carrying wt p53 tumors, PM2 combined with radiotherapy significantly prolonged the median survival by 50%, whereas effects of PM2 therapy on mutant and p53 ^-/- tumors were negligible. PM2-dependent stabilization of p53 was confirmed with <i>ex vivo</i> immunohistochemistry. These data demonstrate the potential of the stapled peptide PM2 as a radiotherapy potentiator <i>in vivo</i> and suggest that clinical application of PM2 with radiotherapy in wt p53 cancers might improve tumor control.<b>Significance:</b> These findings contribute advances to cancer radiotherapy by using novel p53-reactivating stapled peptides as radiosensitizers in wild-type p53 cancers. <i>Cancer Res; 78(17); 5084-93. ©2018 AACR</i>.