• What is MAP2K1?
  • MAP2K1 in Melanoma
  • MEK1 c.362G>C (C121S)
  • 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/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.padiracinnovation.org/content/disease/melanoma/map2k1/ (Updated June 18).

Last Updated: June 18, 2015

MEK1 (MAP2K1) c.362G>C (C121S) 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 C121S mutation among MEK1-mutated melanomas Observed 1 time (Wagle et al. 2011)
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 C121S mutation results in an amino acid substitution at position 121 in MEK1, from a cysteine (C) to a serine (S).

a A patient initially experienced a near-complete response to treatment with vemurafenib; however, the patient relapsed and a tumor biopsy revealed an acquired MEK1 C121S mutation (Wagle et al. 2011). Using a cell line with BRAF V600E and MEK1 C121S mutations, the C121S mutation has also been associated with resistance to vemurafenib, PLX4720 (a compound related to vemurafenib) and AZD6244 (selumetinib; Shi et al. 2012; Wagle et al. 2011).

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.362G>C (C121S) Mutation in Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/map2k1/212/ (Updated June 16).

Last Updated: June 16, 2015

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