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/lung-cancer/map2k1/?tab=0
(Updated December 7).
Last Updated: December 7, 2015
MEK1 (MAP2K1) in Non-Small Cell Lung Cancer (NSCLC)
Somatic mutations in MEK1 (MAP2K1)
have been found in approximately 1% of all NSCLC and are more common in adenocarcinoma than
squamous cell carcinoma (Arcila et al. 2014; Marks et al.
2008). In a retrospective study of 36 MEK1-mutated lung adenocarcinoma
patient cases, MEK1 mutations were more prevalent in tumors from smokers or former
smokers, and there were no other associations with age, sex, race or stage (Arcila et al.
2014). In this series, the most frequently observed mutations were K57N (64%) and
Q56P (19%), and MEK1 mutations were mutually exclusive with mutations in
EGFR, KRAS, BRAF and other driver mutations (Arcila et al.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. MEK1 (MAP2K1) in Non-Small
Cell Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/map2k1/
(Updated June 18).
Last Updated: June 18, 2015
MEK1 (MAP2K1) c.171G>T (K57N) Mutations in Non-Small Cell Lung Cancer (NSCLC)
|Location of mutation
|Frequency of MEK1 mutations
||~1% (Marks et
|Frequency of K57N mutations in
||64% (Arcila et
|Implications for Targeted Therapeutics
|Response to MEK inhibitors
||Unknown at this time
|Response to EGFR TKIs
||Unknown at this timea
|Response to anti-EGFR antibodies
||Unknown at this time
The K57N mutation results in an amino acid change at position 57 in MEK1,
from a lysine (K) to an asparagine (N). This mutation
occurs outside of the kinase domain of
MEK1 (Figure 1). Preclinical data have shown that this mutation leads to constitutive activation of the MAPK
signaling pathway in vitro (Marks et al. 2008).
Clinical characteristics of lung cancer patients with tumors harboring K57N mutations include a strong association with
smoking, but no association with age, sex, race or stage (Arcila et al. 2014).
In vitro studies suggest that the K57N mutation is sensitive to a MEK1 small molecule
non-ATP competitive inhibitor (AZD6244; Marks et al. 2008).
a The presence of MEK1 mutations
has been associated with in vitro resistance to EGFR TKIs (Marks et al. 2008).
However, it should be noted that MEK1 mutations are usually found in tumors wild type
for EGFR, ALK, and other driver mutations.
Figure 1. Schematic of MEK1 K57N mutation. Functional domains of MEK1 are
depicted. D: Docking domain. NES: Nuclear Export Sequence.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. MEK1 (MAP2K1) c.171G>T
(K57N) Mutations in Non-Small Cell Lung Cancer
(NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/map2k1/72/
(Updated January 23).
Last Updated: January 23, 2015
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