Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer

• Published in: Oncogene Vol. 26; no. 22; pp. 3291 - 3310
• Main Authors: Roberts, P J, Der, C J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.05.2007; Nature Publishing Group
• Subjects: Animals; Apoptosis; Autocrine signalling; Cancer; Care and treatment; Cell Biology; Cell differentiation; Cell proliferation; Cell survival; Cellular signal transduction; Drug Delivery Systems - methods; Epidermal growth factor; Epidermal growth factor receptors; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - physiology; Genetic aspects; Genetics; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; MAP kinase; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - physiology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Medicine; Medicine & Public Health; Metabolic pathways; Mutation; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Oncology; Protein kinase; Protein kinase C; Protein kinases; Proteins; raf Kinases - antagonists & inhibitors; raf Kinases - genetics; raf Kinases - physiology; Raf protein; Ras protein; review; Signal transduction; Threonine; Tumorigenesis; Tumors; United States; small molecule inhibitors; Ras; mitogen-activated protein kinases; epidermal growth factor receptor; ERK; monoclonal antibodies
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210422

Mitogen-activated protein kinase (MAPK) cascades are key signaling pathways involved in the regulation of normal cell proliferation, survival and differentiation. Aberrant regulation of MAPK cascades contribute to cancer and other human diseases. In particular, the extracellular signal-regulated kinase (ERK) MAPK pathway has been the subject of intense research scrutiny leading to the development of pharmacologic inhibitors for the treatment of cancer. ERK is a downstream component of an evolutionarily conserved signaling module that is activated by the Raf serine/threonine kinases. Raf activates the MAPK/ERK kinase (MEK)1/2 dual-specificity protein kinases, which then activate ERK1/2. The mutational activation of Raf in human cancers supports the important role of this pathway in human oncogenesis. Additionally, the Raf-MEK-ERK pathway is a key downstream effector of the Ras small GTPase, the most frequently mutated oncogene in human cancers. Finally, Ras is a key downstream effector of the epidermal growth factor receptor (EGFR), which is mutationally activated and/or overexpressed in a wide variety of human cancers. ERK activation also promotes upregulated expression of EGFR ligands, promoting an autocrine growth loop critical for tumor growth. Thus, the EGFR-Ras-Raf-MEK-ERK signaling network has been the subject of intense research and pharmaceutical scrutiny to identify novel target-based approaches for cancer treatment. In this review, we summarize the current status of the different approaches and targets that are under evaluation and development for the therapeutic intervention of this key signaling pathway in human disease.