title: Synthetic lethal interaction between PI3K/Akt/mTOR and Ras/MEK/ERK pathway inhibition in rhabdomyosarcoma.
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.
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Monika Katharina
authors.initials: MK
authors.lastname: Guenther
authors.forename: Ulrike
authors.initials: U
authors.lastname: Graab
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005663:Furans / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D012208:Rhabdomyosarcoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002070:Butadienes; D058534:Class I Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D005663:Furans; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C522973:PI103; C113580:U 0126; C482128:MAP2K2 protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C482125:MAP2K1 protein, human
keywords: Apoptosis; MAPK; PI3K; Rhabdomyosarcoma