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

• Published in: Molecular cancer therapeutics 2015-09, Vol.14 (9), p.1994-2003
• Main Authors: Werner, Lauryn R, Huang, Shyhmin, Francis, David M, Armstrong, Eric A, Ma, Fang, Li, Chunrong, Iyer, Gopal, Canon, Jude, Harari, Paul M
• Format: Article
• Language: English
• Subjects: Acetates - pharmacology; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Apoptosis - radiation effects; Autophagy - drug effects; Autophagy - radiation effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - radiation effects; Cellular Senescence - drug effects; Cellular Senescence - radiation effects; Disease Models, Animal; Humans; Mice; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - radiotherapy; Piperidones - pharmacology; Protein Binding - drug effects; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Radiation Tolerance - drug effects; Radiation, Ionizing; Signal Transduction - drug effects; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-14-1056-T

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.