Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response.

// James A. McCubrey 1 , Linda S. Steelman 1 , William H. Chappell 1 , Stephen L. Abrams 1 , Giuseppe Montalto 2 , Melchiorre Cervello 3 , Ferdinando Nicoletti 4 , Paolo Fagone 4 , Grazia Malaponte 4 , Maria C. Mazzarino 4 , Saverio Candido 4 , Massimo Libra 4 , Jörg Bäsecke 5 , Sanja Mijatovic 6 , Danijela Maksimovic-Ivanic 6 Michele Milella 7 , Agostino Tafuri 8 , Lucio Cocco 9 , Camilla Evangelisti 10 , Francesca Chiarini 10 , Alberto M. Martelli 9,10 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA 2 Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy 3 Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy 4 Department of Biomedical Sciences, University of Catania, Catania, Italy 5 Department of Medicine, University of Göttingen, Göttingen, Germany 6 Department of Immunology, Instititue for Biological Research “Sinisa Stankovic”, University of Belgrade, Belgrade, Serbia 7 Regina Elena National Cancer Institute, Rome, Italy 8 Sapienza, University of Rome, Department of Cellular Biotechnology and Hematology, Rome, Italy 9 Department of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy 10 Institute of Molecular Genetics, National Research Council-Rizzoli Orthopedic Institute, Bologna, Italy Correspondence: James A. McCubrey , email: // Keywords : Targeted Therapy, Therapy Resistance, Mutations, Raf, Akt, PI3K, mTOR(definition) Received : August 12, 2012, Accepted : September 17, 2012, Published : September 20, 2012 Abstract The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors.