Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance

James Andrew McCubrey _, Linda S. Steelman, William H. Chappell, Stephen L. Abrams, Richard A. Franklin, Giuseppe Montalto, Melchiorre Cervello, Massimo Libra, Saverio Candido, Grazia Malaponte, Maria C. Mazzarino, Paolo Fagone, Ferdinando Nicoletti, Jörg Bäsecke, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Michele Milella, Agostino Tafuri, Francesca Chiarini, Camilla Evangelisti, Lucio Cocco and Alberto M. Martelli

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Oncotarget. 2012; 3:1068-1111. https://doi.org/10.18632/oncotarget.659

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James A. McCubrey1, Linda S. Steelman1, William H. Chappell1, Stephen L. Abrams1, Richard A. Franklin1, Giuseppe Montalto2, Melchiorre Cervello3, Massimo Libra4, Saverio Candido4, Grazia Malaponte4, Maria C. Mazzarino4, Paolo Fagone4, Ferdinando Nicoletti4, Jörg Bäsecke5, Sanja Mijatovic6, Danijela Maksimovic-Ivanic6, Michele Milella7, Agostino Tafuri8, Francesca Chiarini9, Camilla Evangelisti9, Lucio Cocco10, Alberto M. Martelli9,10

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 Bio-Medical 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 Institute of Molecular Genetics, National Research Council-Rizzoli Orthopedic Institute, Bologna, Italy

10 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy


James A. McCubrey, email:

Keywords: Targeted Therapy, Therapy Resistance, Cancer Stem Cells, Raf, Akt, PI3K, mTOR

Received: September 12, 2012, Accepted: October 18, 2012, Published: October 20, 2012


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). Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have been investigated in pre-clinical and clinical investigations and then discuss how cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance.

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