Small Molecule Inhibition of MDM2-p53 Interaction Augments Radiation Response in Human Tumors.

Lauryn R Werner,Chunrong Li,David M Francis,Gopal Iyer,Shyhmin Huang,Eric A Armstrong,Paul M Harari,Fang Ma,Jude Canon

doi:10.1158/1535-7163.mct-14-1056-t

Lauryn R Werner, Chunrong Li + Show 7 more

Open Access

https://doi.org/10.1158/1535-7163.mct-14-1056-t

Copy DOI

Abstract

MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We examined the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. AMG 232 effectively inhibited proliferation and enhanced radiosensitivity via inhibition of damage repair signaling. Combined AMG 232 and radiation treatment resulted in the accumulation of γH2AX-related DNA damage and induction of senescence with promotion of apoptotic and/or autophagic cell death. Several molecules involved in senescence, autophagy, and apoptosis were specifically modulated following the combined AMG 232/radiation treatment, including FoxM1, ULK-1, DRAM, and BAX. In vivo xenograft studies confirmed more potent antitumor and antiangiogenesis efficacy with combined AMG 232/radiation treatment than treatment with drug or radiation alone. Taken together, these data identify the capacity of AMG 232 to augment radiation response across a variety of tumor types harboring functional p53.

Highlights

The p53 tumor suppressor is a key modulator of tumorigenesis and a central target in cancer therapy [1]
We further examined the profile of DNA damage at different time points and cell cycle phases via flow cytometric analysis of gH2AX, a marker of DNA double-strand breaks (DSB)
MDM2 inhibitors are a class of p53-activating agents that may be of considerable value in cancer therapeutics

Summary

Introduction

The p53 tumor suppressor is a key modulator of tumorigenesis and a central target in cancer therapy [1]. Referred to as a master regulator, p53 has the ability to initiate a variety of cellular responses upon activation, including cell cycle arrest, senescence, apoptosis, and autophagy [2]. In cancers retaining wild-type (wt) p53, protein function is limited by MDM2, the primary negative regulator of p53. Given the pivotal role of p53 in tumor suppression, several therapeutic strategies to activate p53 by disrupting the negative control by MDM2 have been investigated. Many approaches have been described, including antisense oligonucleotides against MDM2, small molecule inhibitors of MDM2 ubiquitin ligase activity, and small molecule MDM2 inhibitors, which hinder p53–MDM2 interaction [4].

Methods

Results

Conclusion