• What is MAP2K1?
  • MAP2K1 in Lung Cancer
  • MEK1 c.199G>A (D67N)
  • Clinical Trials

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.

mapk-pk13.png

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.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. 2014).

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) 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.199G>A (D67N) Mutations in Non-Small Cell Lung Cancer (NSCLC)

Properties
Location of mutation Exon 2
Frequency of MEK1 mutations in NSCLC ~1% (Marks et al. 2008)
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 D67N mutation results in an amino acid change at position 67 in MEK1, from an aspartic acid (D) 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 (Estep et al. 2007).

Specific clinical characteristics of lung cancer patients with tumors harboring D67N mutations have yet to be described, and clinical responses of patients harboring a D67N lung tumor associated mutation to MEK1 inhibitors are unknown at this time.

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.

mek1-d67n.png

Figure 1.
Schematic of MEK1 D67N mutation. Functional domains of MEK1 are depicted. D: Docking domain. NES: Nuclear Export Sequence.

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) c.199G>A (D67N) Mutations in Non-Small Cell Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/map2k1/60/ (Updated January 23).

Last Updated: January 23, 2015

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