Trametinib
The mitogen-activated protein kinase (MEK MAPK/ERK kinase) signaling pathways play a critical role in regulation of diverse cellular activities, including survival, differentiation, proliferation, motility, and angiogenesis. Therefore, MEK inhibition was
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Abstract
The mitogen-activated protein kinase (MEK MAPK/ERK kinase) signaling pathways play a critical role in regulation of diverse cellular activities, including survival, differentiation, proliferation, motility, and angiogenesis. Therefore, MEK inhibition was recognized as a promising target for antineoplastic therapy. While multiple MEK inhibitors have been tested clinically only trametinib (GSK1120212), an oral MEK inhibitor which is selective for MEK1 and MEK2 has shown promising activity in several clinical trials on melanoma and colorectal cancer and it is being evaluated by the FDA for the treatment of metastatic melanoma. Mechanistically it was shown that trametinib induces cell cycle arrest in vitro. In this overview, important preclinical and clinical data for trametinib are presented including mechanism-based in vitro studies as well as findings from different clinical studies. Future clinical trial in different solid tumor entities will define the therapeutic role of this targeted therapy approach, possibly as a combination with other targeted therapies such as BRAF inhibitors.
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Structure and Mechanism of Action................................................................................... Preclinical Data ................................................................................................................... Clinical Data........................................................................................................................ Toxicity................................................................................................................................ Drug Interactions .................................................................................................................
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R. Zeiser (&) Department of Hematology and Oncology, Freiburg University Medical Center, Albert Ludwigs University, Hugstetterstr. 55, 79106 Freiburg, Germany e-mail: [email protected]
U. M. Martens (ed.), Small Molecules in Oncology, Recent Results in Cancer Research 201, DOI: 10.1007/978-3-642-54490-3_15, Springer-Verlag Berlin Heidelberg 2014
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R. Zeiser
6 Biomarkers........................................................................................................................... 246 7 Summary and Perspectives ................................................................................................. 247 References.................................................................................................................................. 247
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Structure and Mechanism of Action
The mitogen-activated protein kinase (MAPK) signaling pathways involve a family of protein kinases that play critical roles in regulation of diverse cellular activities, including cell proliferation, survival, differentiation, motility, and angiogenesis (Thompson and Lyons 2005). The MAPK pathways transduce signals from various extracellular stimuli (growth factors, hormones, mitogens, cytokines, and environmental
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