MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways

Abstract

// Anne Y. Saiki 1,* , Sean Caenepeel 1,* , Dongyin Yu 1 , Julie A. Lofgren 1 , Tao Osgood 1 , Rebecca Robertson 1 , Jude Canon 1 , Cheng Su 2 , Adrie Jones 3 , Xiaoning Zhao 3 , Chetan Deshpande 4 , Marc Payton 1 , Jebediah Ledell 5 , Paul E. Hughes 1 and Jonathan D. Oliner 1 1 Department of Oncology Research, Amgen, Thousand Oaks, CA 2 Department of Biostatistics, Amgen, Seattle, WA 3 Department of Molecular Structure and Characterization, Amgen, South San Francisco, CA 4 Department of Molecular Sciences and Computational Biology, Amgen, Thousand Oaks, CA 5 Department of Biology, Zalicus, Cambridge, MA * Equal contribution Correspondence: Jonathan D. Oliner, email: // Keywords : MDM2, synergy, MEK, MAPK, PI3K, FOXM1 Received : April 2, 2014 Accepted : April 22, 2014 Published : April 23, 2014 Abstract While MDM2 inhibitors hold great promise as cancer therapeutics, drug resistance will likely limit their efficacy as single agents. To identify drug combinations that might circumvent resistance, we screened for agents that could synergize with MDM2 inhibition in the suppression of cell viability. We observed broad and robust synergy when combining MDM2 antagonists with either MEK or PI3K inhibitors. Synergy was not limited to cell lines harboring MAPK or PI3K pathway mutations, nor did it depend on which node of the PI3K axis was targeted. MDM2 inhibitors also synergized strongly with BH3 mimetics, BCR-ABL antagonists, and HDAC inhibitors. MDM2 inhibitor-mediated synergy with agents targeting these mechanisms was much more prevalent than previously appreciated, implying that clinical translation of these combinations could have far-reaching implications for public health. These findings highlight the importance of combinatorial drug targeting and provide a framework for the rational design of MDM2 inhibitor clinical trials.