title: Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health.
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.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Chappell
authors.forename: Linda S
authors.initials: LS
authors.lastname: Steelman
authors.forename: Jacquelyn M
authors.initials: JM
authors.lastname: Long
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Kempf
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Abrams
authors.forename: Richard A
authors.initials: RA
authors.lastname: Franklin
authors.forename: Jörg
authors.initials: J
authors.lastname: Bäsecke
authors.forename: Franca
authors.initials: F
authors.lastname: Stivala
authors.forename: Marco
authors.initials: M
authors.lastname: Donia
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.forename: Graziella
authors.initials: G
authors.lastname: Malaponte
authors.forename: Maria C
authors.initials: MC
authors.lastname: Mazzarino
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.forename: Danijela
authors.initials: D
authors.lastname: Maksimovic-Ivanic
authors.forename: Sanja
authors.initials: S
authors.lastname: Mijatovic
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Montalto
authors.forename: Melchiorre
authors.initials: M
authors.lastname: Cervello
authors.forename: Piotr
authors.initials: P
authors.lastname: Laidler
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.forename: Agostino
authors.initials: A
authors.lastname: Tafuri
authors.forename: Antonio
authors.initials: A
authors.lastname: Bonati
authors.forename: Camilla
authors.initials: C
authors.lastname: Evangelisti
authors.forename: Lucio
authors.initials: L
authors.lastname: Cocco
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
mesh_terms: D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases; D018631:ras Proteins; C546842:MTOR protein, human; C494929:PTEN protein, human