Abstract
Rhabdomyosarcoma (RMS) frequently exhibits concomitant activation of the PI3K/Akt/mTOR and the Ras/MEK/ERK pathways. Therefore, we investigated whether pharmacological cotargeting of these two key survival pathways suppresses RMS growth. Here, we identify a synthetic lethal interaction between PI3K/Akt/mTOR and Ras/MEK/ERK pathway inhibition in RMS. The dual PI3K/mTOR inhibitor PI103 and the MEK inhibitor UO126 synergize to trigger apoptosis in several RMS cell lines in a highly synergistic manner (combination index <0.1), whereas either agent alone induces minimal cell death. Similarly, genetic knockdown of p110α and MEK1/2 cooperates to induce apoptosis. Molecular studies reveal that cotreatment with PI103/UO126 cooperates to suppress PI3K/Akt/mTOR and Ras/MEK/ERK signaling, whereas either compound alone is not only less effective to inhibit signaling, but even cross-activates the other pathway. Accordingly, PI103 alone increases ERK phosphorylation, while UO126 enhances Akt phosphorylation, consistent with negative crosstalks between these two signaling pathways. Furthermore, PI103/UO126 cotreatment causes downregulation of several antiapoptotic proteins such as XIAP, Bcl-xL and Mcl-1 as well as increased expression and decreased phosphorylation of the proapoptotic protein BimEL, thus shifting the balance towards apoptosis. Consistently, PI103/UO126 cotreatment cooperates to trigger Bax activation, loss of mitochondrial membrane potential, caspase activation and caspase-dependent apoptosis. This identification of a synthetic lethal interaction between PI3K/mTOR and MEK inhibitors has important implications for the development of novel treatment strategies in RMS.
Keywords:
Apoptosis; MAPK; PI3K; Rhabdomyosarcoma.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / metabolism
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Butadienes / pharmacology
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Cell Line, Tumor
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Class I Phosphatidylinositol 3-Kinases
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Dose-Response Relationship, Drug
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Drug Synergism
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Furans / pharmacology
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Humans
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MAP Kinase Kinase 1 / antagonists & inhibitors*
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MAP Kinase Kinase 1 / metabolism
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MAP Kinase Kinase 2 / antagonists & inhibitors*
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MAP Kinase Kinase 2 / metabolism
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Membrane Potential, Mitochondrial / drug effects
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Molecular Targeted Therapy
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Nitriles / pharmacology
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyridines / pharmacology
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Pyrimidines / pharmacology
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RNA Interference
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Rhabdomyosarcoma / enzymology*
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Rhabdomyosarcoma / genetics
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Rhabdomyosarcoma / pathology
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
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Time Factors
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Transfection
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ras Proteins / antagonists & inhibitors*
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ras Proteins / metabolism
Substances
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Apoptosis Regulatory Proteins
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Butadienes
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Furans
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Nitriles
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PI103
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyridines
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Pyrimidines
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U 0126
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MAP2K2 protein, human
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MTOR protein, human
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP2K1 protein, human
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ras Proteins