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
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.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. MEK1 (MAP2K1). My
Cancer Genome https://www.padiracinnovation.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.
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.
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. MEK1 (MAP2K1) in
Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/map2k1/
(Updated June 18).
Last Updated: June 18, 2015
MEK1 (MAP2K1) c.332T>G (I111S) Mutation in Melanoma
|Location of Mutation
||Exon 3 (Ensembl)
|Frequency of MEK1 mutations in
||6–7% (COSMIC; Nikolaev et al.
|Frequency of I111S mutation among
||Observed 1 time (Shi
et al. 2012)
|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 I111S mutation results in an amino acid substitution at position 111 in MEK1,
from an isoleucine (I) to a serine (S).
a In preclinical studies, I111S did not confer resistance to BRAF or MEK
inhibition (Shi et al.
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. MEK1 (MAP2K1) c.332T>G
(I111S) Mutation in Melanoma. My Cancer
(Updated June 16).
Last Updated: June 16, 2015
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