Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer
Abstract
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…
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Efforts shifted to target signaling components downstream of Ras such as Raf-MEK-ERK and PI3K-AKT-mTOR.
“efforts shifted to target signaling components downstream of Ras such as Raf-MEK-ERK mitogen-activated protein kinases4 and the phosphoinositide 3-kinase-AKT-mTOR pathway5.”
From Discovery and characterization of small molecules that target the GTPase Ral (2014) · cites this paper as [4]
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- Authors
- Roberts, P. J., & Der, C. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Der, C J
- ORCID
- Venue
- Oncogene
- Published
- 2007-05-14
- Volume
- 26
- Issue
- 22
- Pages
- 3291-3310
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2011826559
- Cited by
- 2,788
- References
- 8
- Citations by year
- 2026: 60 · 2025: 81 · 2024: 120 · 2023: 116 · 2022: 151 · 2021: 153 · 2020: 127 · 2019: 136 · 2018: 199 · 2017: 171 · 2016: 188 · 2015: 184 · 2014: 195 · 2013: 181 · 2012: 155
- FWCI
- 10.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Raf/MEK/ERK pathway, MAPK signaling, ERK1/2, MEK1/2, Ras GTPase, EGFR, autocrine growth loop, MAPK inhibitors, cancer therapy, oncogenic signaling
- MeSH terms
- Animals, Humans, Neoplasms, Drug Delivery Systems, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Extracellular Signal-Regulated MAP Kinases, raf Kinases
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