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Raf/MEK/ERK Signaling

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Targeted Therapy of Acute Myeloid Leukemia

Part of the book series: Current Cancer Research ((CUCR))

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Abstract

The Ras/Raf/MEK/ERK cascade is often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, and MEK1 are also deregulated by mutations. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. This pathway has profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of this pathway can contribute to: resistance to other pathway inhibitors and chemotherapeutic drugs. Intense scientific, commercial, and clinical interest has developed over the past decade in elucidating the functions of this pathway in leukemia and other blood cancers. Targeting this pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type RAF in the presence of mutant, activated RAS). Furthermore, targeting with inhibitors directed at two constituents of the same pathway may be a more effective approach. This chapter will first describe these pathways and then evaluate potential uses of Raf and MEK inhibitors that have been investigated in pre-clinical and clinical investigations.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Brody Building 5N98C, 27858, Greenville, NC, USA

    James A. McCubrey Ph.D. & Linda S. Steelman

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

    Jörg Bäsecke

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

    Alberto M. Martelli

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

    Alberto M. Martelli

Authors
  1. James A. McCubrey Ph.D.
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  2. Linda S. Steelman
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  3. Jörg Bäsecke
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  4. Alberto M. Martelli
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Corresponding author

Correspondence to James A. McCubrey Ph.D. .

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Editors and Affiliations

  1. Dept. Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Michael Andreeff

Appendices

Conclusions

Pharmaceutical companies have developed inhibitors to the Ras/Raf/MEK/ERK pathway. Initially MEK inhibitors were demonstrated to have the most specificity. However, these inhibitors may have limited effectiveness in treating human cancers, unless the particular cancer proliferates directly in response to the Raf/MEK/ERK pathway. Moreover, MEK inhibitors are often cytostatic as opposed to cytotoxic, thus their ability to function as effective anti-cancer agents in a monotherapeutic setting may be limited, and they may be more effective when combined with chemo or radiotherapy. Raf inhibitors have also been developed and some are being used to treat various cancer patients (e.g., sorafenib). This particular Raf inhibitor also inhibits other receptors and kinases which may be required for the growth of the particular cancer. This promiscuous nature of Sorafenib has contributed to the effectiveness of this particular Raf inhibitor for certain cancers. Raf inhibitors such as vemurafenib, dabrafenib, and GDC-0879 are promising for the treatment of melanoma, CRC, thyroid and other solid cancers and leukemias/lymphomas/myelomas which have mutations at BRAF V600E. However, problems have been identified with certain BRAF mutant allele inhibitors as they will also result in Raf-1 activation if RAS is mutated/amplified of if an exon of BRAF is deleted, or if BRAF is amplified or if there are mutations at MEK1 and other genetic mechanisms. Combination therapy with either a traditional drug/physical treatment or another inhibitor that targets a specific molecule in either the same or different signal transduction pathway are also key approaches for improving the effectiveness and usefulness of MEK and Raf inhibitors.

Some scientists and clinicians have considered that the simultaneous targeting of Raf and MEK by individual inhibitors may be more effective in cancer therapy than just targeting Raf or MEK by themselves (Ricciardi et al. 2012). This is based in part on the fact that there are intricate feed-back loops from ERK which can inhibit Raf and MEK. For example when MEK1 is targeted, ERK1,2 is inhibited and the negative feed-back loop on MEK is broken and activated MEK accumulates. However, if Raf is also inhibited, it may be possible to completely shut down the pathway. This is a rationale for treatment with both MEK and Raf inhibitors. Finally, an emerging concept is the dual targeting of two different signal transduction pathways, Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR for example. This has been explored in some preclinical models and is being investigated in clinical trials. The rationale for the targeting of both pathways may be dependent on the presence of driver mutations in either/or both pathways or in upstream Ras in the particular cancer which can activate both pathways.

Acknowledgments

AMM 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-IR system: new drugs, best drug-drug interactions, mechanisms of resistance and indicators of efficacy”, MIUR PRIN 2008 (2008THTNLC), and MIUR FIRB 2010 (RBAP10447J-003) and 2011 (RBAP11ZJFA_001).

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McCubrey, J., Steelman, L., Bäsecke, J., Martelli, A. (2015). Raf/MEK/ERK Signaling. In: Andreeff, M. (eds) Targeted Therapy of Acute Myeloid Leukemia. Current Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1393-0_14

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