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Review
. 2010 Feb 11:3:8.
doi: 10.1186/1756-8722-3-8.

From basic research to clinical development of MEK1/2 inhibitors for cancer therapy

Christophe Frémin  1 , Sylvain Meloche
Affiliations
Review

From basic research to clinical development of MEK1/2 inhibitors for cancer therapy

Christophe Frémin et al. J Hematol Oncol. .

Abstract

The Ras-dependent Raf/MEK/ERK1/2 mitogen-activated protein (MAP) kinase signaling pathway is a major regulator of cell proliferation and survival. Not surprisingly, hyperactivation of this pathway is frequently observed in human malignancies as a result of aberrant activation of receptor tyrosine kinases or gain-of-function mutations in RAS or RAF genes. Components of the ERK1/2 pathway are therefore viewed as attractive candidates for the development of targeted therapies of cancer. In this article, we briefly review the basic research that has laid the groundwork for the clinical development of small molecules inhibitors of the ERK1/2 pathway. We then present the current state of clinical evaluation of MEK1/2 inhibitors in cancer and discuss challenges ahead.

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Figures

Figure 1
Figure 1
Schematic representation of the Ras-Raf-MEK-ERK1/2 MAP kinase pathway. The figure shows the cascade of activation of the MAP kinases ERK1/ERK2 mediated by growth factor binding to receptor tyrosine kinases. See text for details. GF, growth factor; RTK, receptor tyrosine kinase.
Figure 2
Figure 2
The MAP kinase kinases family. (A) MAP kinases and their upstream MAPKKs. (B) Schematic representation of human MAPKKs. MAPKKs are composed of a kinase catalytic domain (in blue) flanked by N- and C-terminus extensions of varying lengths. The percentage of identity of the kinase domain with MEK1 is indicated. An NES, only present in MEK1 and MEK2, is indicated in yellow.
Figure 3
Figure 3
Genetic alterations of the Ras-dependent ERK1/2 pathway in cancer.
Figure 4
Figure 4
Chemical structures of small molecule MEK1/2 inhibitors.
See this image and copyright information in PMC

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References

    1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. doi: 10.1016/S0092-8674(00)81683-9. - DOI - PubMed
    1. Ray LB, Sturgill TW. Characterization of insulin-stimulated microtubule-associated protein kinase. Rapid isolation and stabilization of a novel serine/threonine kinase from 3T3-L1 cells. J Biol Chem. 1988;263:12721–12727. - PubMed
    1. Raman M, Chen W, Cobb MH. Differential regulation and properties of MAPKs. Oncogene. 2007;26:3100–3112. doi: 10.1038/sj.onc.1210392. - DOI - PubMed
    1. Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors. 2006;24:21–44. doi: 10.1080/02699050500284218. - DOI - PubMed
    1. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22:153–183. doi: 10.1210/er.22.2.153. - DOI - PubMed

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