Advances in Targeting Signal Transduction Pathways.

James Andrew McCubrey _, Linda S Steelman, William H Chappell, Lin Sun, Nicole M Davis, Stephen L Abrams, Richard A Franklin, Lucio Cocco, Camilla Evangelisti, Francesca Chiarini, Alberto M Martelli, Massimo Libra, Saverio Candido, Grazia Malaponte, Maria C Mazzarino, Paolo Fagone, Marco Donia, Ferdinando Nicoletti, Jerry Polesel, Renato Talamini, Jorg Basecke, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Michele Milella, Agostino Tafuri, Joanna Dulińska-Litewka, Piotr Laidler, Antonio B D'Assoro, Lyudmyla Drobot, Kazuo Umezawa, Giuseppe Montalto, Melchiorre Cervello and Zoya N Demidenko

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Oncotarget. 2012; 3:1505-1521. https://doi.org/10.18632/oncotarget.802

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James A. McCubrey1, Linda S. Steelman1, William H. Chappell1, Lin Sun1,2, Nicole M. Davis1, Stephen L. Abrams1, Richard A. Franklin1, Lucio Cocco3, Camilla Evangelisti4, Francesca Chiarini4, Alberto M. Martelli3,4, Massimo Libra5, Saverio Candido5, Giovanni Ligresti5, Grazia Malaponte5, Maria C. Mazzarino5, Paolo Fagone5, Marco Donia5, Ferdinando Nicoletti5, Jerry Polesel6, Renato Talamini6, Jörg Bäsecke7, Sanja Mijatovic8, Danijela Maksimovic-Ivanic8, Michele Milella9, Agostino Tafuri10, Joanna Dulińska-Litewka11, Piotr Laidler11, Antonio B. D’Assoro12, Lyudmyla Drobot13, Kazuo Umezawa14, Giuseppe Montalto15, Melchiorre Cervello16, and Zoya N. Demidenko17.

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


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


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.

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