Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy

L. S. Steelman, R. A. Franklin, S. L. Abrams, W. Chappell, C. R. Kempf, J. Bäsecke, F. Stivala, M. Donia, P. Fagone, F. Nicoletti, M. Libra, P. Ruvolo, V. Ruvolo, C. Evangelisti, A. M. Martelli, J. A. McCubrey

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1080-1094
Number of pages15
JournalLeukemia
Volume25
Issue number7
DOIs
Publication statusPublished - Jul 2011

Keywords

  • ERK
  • Raf
  • Ras
  • resistance
  • targeted therapy
  • therapeutic sensitivity

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Fingerprint Dive into the research topics of 'Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy'. Together they form a unique fingerprint.

  • Cite this

    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., & McCubrey, J. A. (2011). Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia, 25(7), 1080-1094. https://doi.org/10.1038/leu.2011.66