Signaling Through RAS-RAF-MEK-ERK: from Basics to Bedside

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Abstract:

Aberrant signaling caused by mutations in the RAS-RAF-MEK-ERK pathway and its upstream activators critically contributes to human tumor development. Strategies, which aim at inhibiting hyperactive signaling molecules, appear conceptually straight forward, but their translation into clinical practice has been hampered by many setbacks. Understanding structure, function and regulation of this intracellular pathway as well as its crosstalk with other signaling activities in the cell will be essential to ensure reasonable usage of new therapeutic possibilities. This review provides an understanding of this signaling cascade as revealed by genetic and biochemical approaches and discusses the existing or arising possibilities to interfere with unphysiological activation in cancer. Signaling aberrations and signal transduction therapies will be discussed exemplary for two types of hematological neoplasia, acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS). In the future understanding the role of tumor stem cells, both as a source of tumor recurrence and tumor heterogeneity, the signals controlling their fate as well as epigenetic changes in cancer will be the next critical steps to further advance the applicability of these novel therapeutic strategies.

Keywords: BAY 43-9006; C-RAF; acute myeloid leukemia; cytoplasmic cascade; guanine nucleotide exchange factors (GEFs); non-receptor protein tyrosine kinase

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986707780059670

Affiliations: Daniel-Swarovski-Research Laboratory, Department of General- and Transplant Surgery, Innsbruck Medical University (IMU), Innrain 66, 6020 Innsbruck, Austria.

Publication date: February 1, 2007

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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