Still more challenging, many tumors fail to exhibit even an initial response to such therapies, despite harboring clonal oncogenic alterations in the genes or signaling pathways against which these agents are targeted. Following initial pharmacologic tumor debulking, rare, pre-existing subclones of drug-resistant tumor cells typically expand to repopulate the tumor, often within months of the initiation of targeted therapy. However, these therapeutic benefits are rarely durable. ![]() These findings highlight the importance of combinatorial drug targeting and provide a framework for the rational design of MDM2 inhibitor clinical trials.Ĭancer therapies targeting tumor-specific genetic alterations have shown clinical promise, in some cases eliciting remarkable tumor regressions and accompanying improvements in survival. 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. MDM2 inhibitors also synergized strongly with BH3 mimetics, BCR-ABL antagonists, and HDAC 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. We observed broad and robust synergy when combining MDM2 antagonists with either MEK or PI3K inhibitors. To identify drug combinations that might circumvent resistance, we screened for agents that could synergize with MDM2 inhibition in the suppression of cell viability. While MDM2 inhibitors hold great promise as cancer therapeutics, drug resistance will likely limit their efficacy as single agents. Received: ApAccepted: ApPublished: ApAbstract Keywords: MDM2, synergy, MEK, MAPK, PI3K, FOXM1 Oliner 1ġ Department of Oncology Research, Amgen, Thousand Oaks, CAĢ Department of Biostatistics, Amgen, Seattle, WAģ Department of Molecular Structure and Characterization, Amgen, South San Francisco, CAĤ Department of Molecular Sciences and Computational Biology, Amgen, Thousand Oaks, CAĥ Department of Biology, Zalicus, Cambridge, MA 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. Saiki 1,*, Sean Caenepeel 1,*, Dongyin Yu 1, Julie A.
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