1. Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy
- Author
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Ferdinando Nicoletti, Franca Stivala, Linda S. Steelman, Marco Donia, Camilla Evangelisti, Steve L. Abrams, Am Martelli, Peter P. Ruvolo, William H. Chappell, James A. McCubrey, Vivian Ruvolo, Richard A. Franklin, Paolo Fagone, C. R. Kempf, Jörg Bäsecke, Massimo Libra, Steelman L.S., Franklin R.A., Abrams S.L., Chappell W., Kempf C.R., Bäsecke J., Stivala F., Donia M., Fagone P., Nicoletti F., Libra M., Ruvolo P., Ruvolo V., Evangelisti C., Martelli A.M., and McCubrey J.A.
- Subjects
MAPK/ERK pathway ,Cancer Research ,MAP Kinase Signaling System ,Antineoplastic Agents ,Apoptosis ,raf ,ERK ,Raf ,Ras ,resistance ,targeted therapy ,therapeutic sensitivity ,Models, Biological ,erk ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,TARGETED THERAPY ,Anti-apoptotic Ras signalling cascade ,Humans ,PTEN ,Molecular Targeted Therapy ,HRAS ,c-Raf ,Extracellular Signal-Regulated MAP Kinases ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Phosphoinositide-3 Kinase Inhibitors ,030304 developmental biology ,Mitogen-Activated Protein Kinase Kinases ,0303 health sciences ,Leukemia ,biology ,Gene Expression Regulation, Leukemic ,Chemistry ,Kinase ,Hematology ,Neoplasm Proteins ,3. Good health ,Cell biology ,Oncology ,Drug Resistance, Neoplasm ,Drug Design ,030220 oncology & carcinogenesis ,ras Proteins ,biology.protein ,raf Kinases ,ra ,Cell Division - 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.
- Published
- 2011