title: Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy.
abstract: The Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway is often implicated in sensitivity and resistance to leukemia therapy. Dysregulated signaling through the Ras/Raf/MEK/ERK pathway is often the result of genetic alterations in critical components in this pathway as well as mutations at upstream growth factor receptors. Unrestricted leukemia proliferation and decreased sensitivity to apoptotic-inducing agents and chemoresistance are typically associated with activation of pro-survival pathways. Mutations in this pathway and upstream signaling molecules can alter sensitivity to small molecule inhibitors targeting components of this cascade as well as to inhibitors targeting other key pathways (for example, phosphatidylinositol 3 kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/Akt/mammalian target of rapamycin (mTOR)) activated in leukemia. Similarly, PI3K mutations can result in resistance to inhibitors targeting the Ras/Raf/MEK/ERK pathway, indicating important interaction points between the pathways (cross-talk). Furthermore, the Ras/Raf/MEK/ERK pathway can be activated by chemotherapeutic drugs commonly used in leukemia therapy. This review discusses the mechanisms by which abnormal expression of the Ras/Raf/MEK/ERK pathway can contribute to drug resistance as well as resistance to targeted leukemia therapy. Controlling the expression of this pathway could improve leukemia therapy and ameliorate human health.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Steelman
authors.forename: R A
authors.initials: RA
authors.lastname: Franklin
authors.forename: S L
authors.initials: SL
authors.lastname: Abrams
authors.forename: W
authors.initials: W
authors.lastname: Chappell
authors.forename: C R
authors.initials: CR
authors.lastname: Kempf
authors.forename: J
authors.initials: J
authors.lastname: Bäsecke
authors.forename: F
authors.initials: F
authors.lastname: Stivala
authors.forename: M
authors.initials: M
authors.lastname: Donia
authors.forename: P
authors.initials: P
authors.lastname: Fagone
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
authors.forename: M
authors.initials: M
authors.lastname: Libra
authors.forename: P
authors.initials: P
authors.lastname: Ruvolo
authors.forename: V
authors.initials: V
authors.lastname: Ruvolo
authors.forename: C
authors.initials: C
authors.lastname: Evangelisti
authors.forename: A M
authors.initials: AM
authors.lastname: Martelli
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048490:raf Kinases; D018631:ras Proteins