Advances in Targeting Signal Transduction Pathways

// James A. McCubrey 1 , Linda S. Steelman 1 , William H. Chappell 1 , Lin Sun 1,2 , Nicole M. Davis 1 , Stephen L. Abrams 1 , Richard A. Franklin 1 , Lucio Cocco 3 , Camilla Evangelisti 4 , Francesca Chiarini 4 , Alberto M. Martelli 3,4 , Massimo Libra 5 , Saverio Candido 5 , Giovanni Ligresti 5 , Grazia Malaponte 5 , Maria C. Mazzarino 5 , Paolo Fagone 5 , Marco Donia 5 , Ferdinando Nicoletti 5 , Jerry Polesel 6 , Renato Talamini 6 , Jörg Bäsecke 7 , Sanja Mijatovic 8 , Danijela Maksimovic-Ivanic 8 , Michele Milella 9 , Agostino Tafuri 10 , Joanna Dulińska-Litewka 11 , Piotr Laidler 11 , Antonio B. D’Assoro 12 , Lyudmyla Drobot 13 , Kazuo Umezawa 14 , Giuseppe Montalto 15 , Melchiorre Cervello 16 , and Zoya N. Demidenko 17 . 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University 2 Department of Communication Sciences and Disorders, College of Allied Health Sciences, East Carolina University, Greenville, North Carolina, USA 3 Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy 4 Institute of Molecular Genetics, National Research Council-IOR, Bologna, Italy 5 Department of Bio-Medical Sciences, University of Catania, Catania, Italy 6 Unit of Epidemiology and Biostatistics, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy. 7 Department of Medicine, University of Göttingen, Göttingen, Germany 8 Department of Immunology, Instititue for Biological Research “Sinisa Stankovic”, University of Belgrade, Belgrade, Serbia 9 Regina Elena National Cancer Institute, Rome, Italy 10 Sapienza, University of Rome, Department of Cellular Biotechnology and Hematology, Rome, Italy 11 Chair of Medical Biochemistry, Jagiellonian University Medical College, Kraków, Poland. 12 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA. 13 Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine 14 Department of Molecular Target Medicine Screening, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan 15 Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy 16 Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy 17 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, USA Correspondence: James A. McCubrey, email: // Keywords : Targeted Therapy, Therapy Resistance, Cancer Stem Cells, Raf, Akt, PI3K, mTOR, AMPK, Metformin Received : December 27, 2012, Accepted : December 28, 2012, Published : December 30, 2012 Abstract Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies.