title: MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways.
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.
authors.affiliation: Department of Oncology Research, Amgen, Thousand Oaks, CA.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Saiki
authors.forename: Sean
authors.initials: S
authors.lastname: Caenepeel
authors.forename: Dongyin
authors.initials: D
authors.lastname: Yu
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lofgren
authors.forename: Tao
authors.initials: T
authors.lastname: Osgood
authors.forename: Rebecca
authors.initials: R
authors.lastname: Robertson
authors.forename: Jude
authors.initials: J
authors.lastname: Canon
authors.forename: Cheng
authors.initials: C
authors.lastname: Su
authors.forename: Adrie
authors.initials: A
authors.lastname: Jones
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhao
authors.forename: Chetan
authors.initials: C
authors.lastname: Deshpande
authors.forename: Marc
authors.initials: M
authors.lastname: Payton
authors.forename: Jebediah
authors.initials: J
authors.lastname: Ledell
authors.forename: Paul E
authors.initials: PE
authors.lastname: Hughes
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Oliner
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2