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 MilellaAgostino Tafuri, Antonio Bonati, Camilla Evangelisti, Lucio Cocco, Alberto M. Martelli, James A. McCubrey

Research output: Contribution to journalArticle

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). 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.

Original languageEnglish
Pages (from-to)135-164
Number of pages30
JournalOncotarget
Volume2
Issue number3
Publication statusPublished - 2011

Keywords

  • Aging
  • Akt
  • Cancer stem cells
  • Combination therapy
  • Drug resistance
  • mTOR
  • Pi3K
  • Raf
  • Senescence
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

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  • Cite this

    Chappell, W. H., Steelman, L. S., Long, J. M., Kempf, R. C., Abrams, S. L., Franklin, R. A., Bäsecke, J., Stivala, F., Donia, M., Fagone, P., Malaponte, G., Mazzarino, M. C., Nicoletti, F., Libra, M., Maksimovic-Ivanic, D., Mijatovic, S., Montalto, G., Cervello, M., Laidler, P., ... McCubrey, J. A. (2011). Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: Rationale and importance to inhibiting these pathways in human health. Oncotarget, 2(3), 135-164.