pi103 and Rhabdomyosarcoma

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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Butadienes; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Furans; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Membrane Potential, Mitochondrial; Molecular Targeted Therapy; Nitriles; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridines; Pyrimidines; ras Proteins; Rhabdomyosarcoma; RNA Interference; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Transfection