title: Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response.
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). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA. mccubreyj@ecu.edu
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: Linda S
authors.initials: LS
authors.lastname: Steelman
authors.forename: William H
authors.initials: WH
authors.lastname: Chappell
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Abrams
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Montalto
authors.forename: Melchiorre
authors.initials: M
authors.lastname: Cervello
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.forename: Grazia
authors.initials: G
authors.lastname: Malaponte
authors.forename: Maria C
authors.initials: MC
authors.lastname: Mazzarino
authors.forename: Saverio
authors.initials: S
authors.lastname: Candido
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.forename: Jörg
authors.initials: J
authors.lastname: Bäsecke
authors.forename: Sanja
authors.initials: S
authors.lastname: Mijatovic
authors.forename: Danijela
authors.initials: D
authors.lastname: Maksimovic-Ivanic
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.forename: Agostino
authors.initials: A
authors.lastname: Tafuri
authors.forename: Lucio
authors.initials: L
authors.lastname: Cocco
authors.forename: Camilla
authors.initials: C
authors.lastname: Evangelisti
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiarini
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein 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