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

Leukemia volume 25, pages 1080–1094 (2011)Cite this article

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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.

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Acknowledgements

This work was supported in part by grants from Fondazione del Monte di Bologna e Ravenna, MinSan 2008, ‘Molecular therapy in pediatric sarcomas and leukemias against IGF-1 receptor system’ (PRIN 2008 and FIRB 2010 (RBAP10447J)) to AMM.

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  1. Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA

    L S Steelman, R A Franklin, S L Abrams, W Chappell & J A McCubrey

  2. Department of Physics, East Carolina University, Greenville, NC, USA

    L S Steelman & C R Kempf

  3. Department of Medicine, University of Göttingen, Göttingen, Germany

    J Bäsecke

  4. Department of Biomedical Sciences, University of Catania, Catania, Italy

    F Stivala, M Donia, P Fagone, F Nicoletti & M Libra

  5. Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P Ruvolo & V Ruvolo

  6. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell’Apparato Locomotore, Università di Bologna, Bologna, Italy

    C Evangelisti & A M Martelli

  7. IGM-CNR, Sezione di Bologna, C/o IOR, Bologna, Italy

    A M Martelli

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Steelman, L., Franklin, R., Abrams, S. et al. Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia 25, 1080–1094 (2011). https://doi.org/10.1038/leu.2011.66

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