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5618796 
Journal Article 
Synthetic lethal interaction between PI3K/Akt/mTOR and Ras/MEK/ERK pathway inhibition in rhabdomyosarcoma 
Guenther, MK; Graab, U; Fulda, S 
2013 
Yes 
Cancer Letters
ISSN: 0304-3835
EISSN: 1872-7980 
Cancer Lett. 
337 
2 
200-9. [Cancer letters] 
English 
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. 
Antineoplastic Combined Chemotherapy Protocols/pharmacology; Apoptosis/drug effects; Apoptosis Regulatory Proteins/metabolism; Butadienes/pharmacology; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism; Furans/pharmacology; MAP Kinase Kinase 1/antagonists & inhibitors/metabolism; MAP Kinase Kinase 2/antagonists & inhibitors/metabolism; Membrane Potential, Mitochondrial/drug effects; Molecular Targeted Therapy; Nitriles/pharmacology; Phosphatidylinositol 3-Kinases/antagonists & inhibitors/genetics/metabolism; Phosphorylation; Protein Kinase Inhibitors/pharmacology; Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism; Pyridines/pharmacology; Pyrimidines/pharmacology; RNA Interference; Rhabdomyosarcoma/enzymology/genetics/pathology; Signal Transduction/drug effects; TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism; Time Factors; Transfection; ras Proteins/antagonists & inhibitors/metabolism; Apoptosis; Rhabdomyosarcoma