title: Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways.
abstract: Chemotherapy remains a commonly used therapeutic approach for many cancers. Indeed chemotherapy is relatively effective for treatment of certain cancers and it may be the only therapy (besides radiotherapy) that is appropriate for certain cancers. However, a common problem with chemotherapy is the development of drug resistance. Many studies on the mechanisms of drug resistance concentrated on the expression of membrane transporters and how they could be aberrantly regulated in drug resistant cells. Attempts were made to isolate specific inhibitors which could be used to treat drug resistant patients. Unfortunately most of these drug transporter inhibitors have not proven effective for therapy. Recently the possibilities of more specific, targeted therapies have sparked the interest of clinical and basic researchers as approaches to kill cancer cells. However, there are also problems associated with these targeted therapies. Two key signaling pathways involved in the regulation of cell growth are the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways. Dysregulated signaling through these pathways is often the result of genetic alterations in critical components in these pathways as well as mutations in upstream growth factor receptors. Furthermore, these pathways may be activated by chemotherapeutic drugs and ionizing radiation. This review documents how their abnormal expression can contribute to drug resistance as well as resistance to targeted therapy. This review will discuss in detail PTEN regulation as this is a critical tumor suppressor gene frequently dysregulated in human cancer which contributes to therapy resistance. Controlling the expression of these pathways could improve cancer therapy and ameliorate human health.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858, 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: C Ruth
authors.initials: CR
authors.lastname: Kempf
authors.forename: William H
authors.initials: WH
authors.lastname: Chappell
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Abrams
authors.forename: Franca
authors.initials: F
authors.lastname: Stivala
authors.forename: Graziella
authors.initials: G
authors.lastname: Malaponte
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.forename: Jörg
authors.initials: J
authors.lastname: Bäsecke
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: Lucio
authors.initials: L
authors.lastname: Cocco
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; 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 / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases