Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health

William H. Chappell, Linda S. Steelman, Jacquelyn M. Long, Ruth C. Kempf, Stephen L. Abrams, Richard A. Franklin, Jörg Bäsecke, Franca Stivala, Marco Donia, Paolo Fagone, Graziella Malaponte, Maria C. Mazzarino, Ferdinando Nicoletti, Massimo Libra, Danijela Maksimovic-Ivanic, Sanja Mijatovic, Giuseppe Montalto, Melchiorre Cervello, Piotr Laidler, Michele Milella, Agostino Tafuri, Antonio Bonati, Camilla Evangelisti, Lucio Cocco, Alberto M. Martelli and James A. McCubrey _

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Oncotarget. 2011; 2:135-164. https://doi.org/10.18632/oncotarget.240

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William H. Chappell1, Linda S. Steelman1,2, Jacquelyn M. Long2, Ruth C. Kempf2, Stephen L. Abrams1, Richard A. Franklin1, Jörg Bäsecke3, Franca Stivala4, Marco Donia4, Paolo Fagone4, Graziella Malaponte4, Maria C. Mazzarino4, Ferdinando Nicoletti4, Massimo Libra4, Danijela Maksimovic-Ivanic5, Sanja Mijatovic5, Giuseppe Montalto6, Melchiorre Cervello7, Piotr Laidler8, Michele Milella9, Agostino Tafuri10, Antonio Bonati11, Camilla Evangelisti12, Lucio Cocco12, Alberto M. Martelli12,13, and James A. McCubrey1

1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University

2 Department of Physics, Greenville, NC 27858 USA

3 Department of Medicine University of Göttingen, Göttingen, Germany

4 Department of Biomedical Sciences, University of Catania, Catania, Italy

5 Department of Immunology, Institute for Biological Research “Sinisa Stankovic”, University of Belgrade, Belgrade, Serbia

6 Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy

7 Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy

8 Department of Medical Biochemistry Jagiellonian University Medical College, Krakow, Poland

9 Regina Elena Cancer Center, Via Elio Chianesi n.53, Rome 00144, Italy

10 University of Rome, La Sapienza, Department of Hematology-Oncology, Via Benevento 6, Rome 99161, Italy

11 University Hospital of Parma, Unit of Hematology and Bone-Marrow Transplantation, Via Gramsi n.14, Parma 43100, Italy

12 Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell’Apparato Locomotore, Università di Bologna, Bologna, Italy

13 IGM-CNR, Sezione di Bologna, C/o IOR, Bologna, Italy

Keywords: Targeted Therapy, Combination Therapy, Drug Resistance, Cancer Stem Cells, Aging, Senescence, Raf, Akt, PI3K, mTOR

Received: February 25, 2011; Accepted: March 10, 2011; Published: March 11, 2011;


James A. McCubrey, e-mail:


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). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging.

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