title: Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance.
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). 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.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
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: Richard A
authors.initials: RA
authors.lastname: Franklin
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Montalto
authors.forename: Melchiorre
authors.initials: M
authors.lastname: Cervello
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.forename: Saverio
authors.initials: S
authors.lastname: Candido
authors.forename: Grazia
authors.initials: G
authors.lastname: Malaponte
authors.forename: Maria C
authors.initials: MC
authors.lastname: Mazzarino
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
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: Francesca
authors.initials: F
authors.lastname: Chiarini
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
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C546842:MTOR protein, human; C494929:PTEN protein, human