Abstract
The Ras/Raf/MEK/extracellular signal regulated kinase (ERK) (Ras/mitogen-activated protein kinases (MAPK)) signal transduction pathway is a crucial mediator of many fundamental biological processes, including cellular proliferation, survival, angiogenesis and migration. Aberrant signalling through the Ras/MAPK cascade is common in a wide array of malignancies, including multiple myeloma (MM), making it an appealing candidate for the development of novel targeted therapies. In this review, we explore our current understanding of the Ras/MAPK pathway and its role in MM. Additionally, we summarise the current status of small molecule inhibitors of MEK under clinical evaluation, and discuss future approaches required to optimise their use.
Highlights
Mitogen-activated protein kinases (MAPKs) are a family of ubiquitously expressed serine/threonine kinases that transmit diverse cell surface signals throughout the cell
MEK lies at a critical juncture within the Ras/MAPK pathway, having a limited number of direct upstream MAP3K activators and ERK1/2 as its only known cellular targets, thereby making it an attractive target for cancer therapy
AZD6244.79 Collectively, these results provide a rationale for tumour models suggest that combination regimes are required combining inhibitors of the JAK/STAT pathway and MEK inhibitors to maximise the effectiveness of MEK inhibitors in MM
Summary
The Ras/Raf/MEK/extracellular signal regulated kinase (ERK) (Ras/mitogen-activated protein kinases (MAPK)) signal transduction pathway is a crucial mediator of many fundamental biological processes, including cellular proliferation, survival, angiogenesis and migration. Aberrant signalling through the Ras/MAPK cascade is common in a wide array of malignancies, including multiple myeloma (MM), making it an appealing candidate for the development of novel targeted therapies. We explore our current understanding of the Ras/MAPK pathway and its role in MM. We summarise the current status of small molecule inhibitors of MEK under clinical evaluation, and discuss future approaches required to optimise their use. Blood Cancer Journal (2013) 3, e105; doi:10.1038/bcj.2013.1; published online 22 March 2013 Keywords: multiple myeloma; MEK inhibitors; Ras/MAPK; MEK
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