MEK1 (MAP2K1)
MEK1 (also known as MAP2K1) is a serine-threonine protein kinase that is a central mediator in the MAP kinase signaling pathway. As part of the MAP kinase pathway, MEK1 is involved in many cellular processes, including cell proliferation, differentiation, and transcriptional regulation.

Figure 1. Schematic of the MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.
Related Pathways
Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. MEK1 (MAP2K1). My Cancer Genome https://www.mycancergenome.org/content/disease/melanoma/map2k1/?tab=0 (Updated December 7).
Last Updated: December 7, 2015
MEK1 (MAP2K1) in Melanoma
Somatic mutations in MEK1 have been found in 6–7% of malignant melanomas (COSMIC; Nikolaev et al. 2012). The prevalence of MEK1 mutations in different melanoma subtypes is not yet known. However, most of the reported MEK1 mutations involve C>T and G>A nucleotide changes, which frequently result from exposure to UV radiation (Emery et al. 2009; Nikolaev et al. 2012).
MEK1 mutations often occur together with BRAF or NRAS mutations (Emery et al. 2009; Nikolaev et al. 2012; Shi et al. 2012).
While several MEK inhibitors or multi-kinase inhibitors that target MEK1 are available, little is currently known about the role of MEK1 mutations play in treatment of melanoma (Shi et al. 2012). Some have proposed that MEK1 mutations in BRAF V600E-mutated tumors confer resistance to BRAF inhibition (Emery et al. 2009; Greger et al. 2012; Wagle et al. 2011). However, others have proposed that MEK1 mutations may not play a significant role in sensitivity or resistance to BRAF and MEK1 inhibition (Shi et al. 2012). Clinically, BRAF inhibitors have been investigated in combination with MEK inhibitors in subsets of patients with BRAF V600E mutation-positive melanoma previously resistant to BRAF inhibitors (Johnson et al. 2014; Ribas et al. 2014).
Contributors: Christine M. Lovly, M.D., Ph.D., William Pao, M.D., Ph.D. (through April 2014), Jeff Sosman, M.D.
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. MEK1 (MAP2K1) in Melanoma. My Cancer Genome https://www.mycancergenome.org/content/disease/melanoma/map2k1/ (Updated June 18).
Last Updated: June 18, 2015
MEK1 (MAP2K1) c.371C>T (P124L) Mutation in Melanoma
Properties |
Location of Mutation
|
Exon 3 (Ensembl) |
Frequency of MEK1 mutations in melanoma |
6–7% (COSMIC; Nikolaev et al. 2012) |
Frequency of P124L mutation among MEK1-mutated melanomas |
Observed 1 time (Emery et al. 2009) |
Implications for Targeted Therapeutics |
Response to BRAF inhibitors |
Unknown at this timea
|
Response to MEK inhibitors |
Unknown at this timea
|
Response to KIT inhibitors |
Unknown at this time |
The P124L mutation results in an amino acid substitution at position 124 in MEK1, from a proline (P) to a leucine (L).
a P124L has been observed in a patient’s tumor following treatment with selumetinib (Emery et al. 2009). As a result, it was suggested that this mutation may confer resistance to MEK and BRAF inhibitors. However, the cell line developed from this patient’s tumor, M307, also showed strong COT expression, which has been proposed to confer de novo resistance to BRAF inhibition (Emery et al. 2009; Johannessen et al. 2010). In addition, a related mutation, P124S, is not the primary determinant of resistance to MEK and BRAF inhibition (Shi et al. 2012). In an observational study, 123 patients whose BRAF V600E-positive melanoma harbored pre-treatment P124 mutations demonstrated decreased response compared with patients with BRAF V600E-positive melanoma wildtype for P124 mutations to BRAF inhibitor treatment (Carlino et al. 2014).
Contributors: Christine M. Lovly, M.D., Ph.D., William Pao, M.D., Ph.D. (through April 2014), Jeff Sosman, M.D.
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. MEK1 (MAP2K1) c.371C>T (P124L) Mutation in Melanoma. My Cancer Genome https://www.mycancergenome.org/content/disease/melanoma/map2k1/213/ (Updated June 16).
Last Updated: June 16, 2015
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