Molecule Information

General Information of the Molecule (ID: Mol00510)

• Name: MAPK/ERK kinase 2 (MEK2) ,Homo sapiens
• Synonyms: MAP kinase kinase 2; MAPKK 2; ERK activator kinase 2; MAPK/ERK kinase 2; MEK 2; MEK2; MKK2; PRKMK2
• Molecule Type: Protein
• Gene Name: MAP2K2
• Gene ID: 5605
• Location: chr19:4090321-4124122[-]
• Sequence:
  MLARRKPVLPALTINPTIAEGPSPTSEGASEANLVDLQKKLEELELDEQQKKRLEAFLTQ
  KAKVGELKDDDFERISELGAGNGGVVTKVQHRPSGLIMARKLIHLEIKPAIRNQIIRELQ
  VLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKEAKRIPEEILGKVSIAVLRG
  LAYLREKHQIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMAPERLQ
  GTHYSVQSDIWSMGLSLVELAVGRYPIPPPDAKELEAIFGRPVVDGEEGEPHSISPRPRP
  PGRPVSGHGMDSRPAMAIFELLDYIVNEPPPKLPNGVFTPDFQEFVNKCLIKNPAERADL
  KMLTNHTFIKRSEVEEVDFAGWLCKTLRLNQPGTPTRTAV
• Function: Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases. Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation.
• Uniprot ID: MP2K2_HUMAN
• Ensembl ID: ENSG00000126934
• HGNC ID: HGNC:6842

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Dabrafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [1]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Dabrafenib
• Molecule Alteration: Missense mutation; p.N126D
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole Exome Sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: We identified four mutations involving the MAP2k2 gene (which encodes the MEk2 kinase) in drug-resistant melanoma specimens. Like its homologue MEk1, MEk2 is situated immediately downstream of RAF proteins in the MAPk pathway.

Disease Class: Melanoma [1]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Dabrafenib
• Molecule Alteration: Missense mutation; p.L46F
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole Exome Sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: We identified four mutations involving the MAP2k2 gene (which encodes the MEk2 kinase) in drug-resistant melanoma specimens. Like its homologue MEk1, MEk2 is situated immediately downstream of RAF proteins in the MAPk pathway.

Disease Class: Melanoma [2]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Dabrafenib
• Molecule Alteration: Missense mutation; p.C125S
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: One portion of the tumour screened by capillary sequencing of reverse transcription PCR (RT-PCR) products contained both the MEk1G128D and MEk2C125S mutations and demonstrated MAPk reactivation.

Disease Class: Melanoma [3]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Dabrafenib
• Molecule Alteration: Missense mutation; p.Q60P
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Recent whole-exome and RNA sequencing studies have identified a wide array of acquired mutations that confer resistance, including those that reactivate the MAPk pathway (NRAS, kRAS, and MEk1/2 mutations, NF1 loss, BRAF amplification, and BRAF splice variants) and those that activate the PI3k pathway (PIk3CA, PIk3R1, and AkT1/2 mutations and PTEN loss). Of the 6 samples with putative resistance-conferring alterations, 15C harbored an acquired missense PTENR159S mutation in the phosphatase domain, 25C harbored a known acquired MEkQ60L mutation.

Disease Class: Melanoma [2]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Dabrafenib
• Molecule Alteration: Missense mutation; p.E207K
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: The Prog that did not show evidence of MAPk reactivation by GSEA had two identified resistance mechanisms (MEk2E207k and NRASG12D), but both variants occurred at low frequency (13 and 15% allelic frequency, respectively, by whole-exome sequencing), suggesting heterogeneity within the Prog metastasis.

Vemurafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [4]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.F57C
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Capillary sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: Selecting sequential drugs based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved responses, and first-line therapies targeting multiple pathways will be required. Functional analyses confirmed that MEk1k57E and MEk2F57C mutants restored extracellular signal-regulated kinase (ERk) activation in the presence of dabrafenib, whereas MEk1G176S did not alter melanoma cell sensitivity to dabrafenib.

Disease Class: Melanoma [1]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.V35M
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole Exome Sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: We identified four mutations involving the MAP2k2 gene (which encodes the MEk2 kinase) in drug-resistant melanoma specimens. Like its homologue MEk1, MEk2 is situated immediately downstream of RAF proteins in the MAPk pathway.

Disease Class: Melanoma [1]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.C125S
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole Exome Sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: We identified four mutations involving the MAP2k2 gene (which encodes the MEk2 kinase) in drug-resistant melanoma specimens. Like its homologue MEk1, MEk2 is situated immediately downstream of RAF proteins in the MAPk pathway.

Clinical Trial Drug(s) 1 drug(s) in total

PD-0325901

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [5]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: PD-0325901
• Molecule Alteration: Missense mutation; p.V215E
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAS/RAF/MEk signaling pathway; Activation; hsa04010
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: HCT-116 MEk-R cells; Colon; Homo sapiens (Human); CVCL_V401
• Experiment for Molecule Alteration: Exome sequencing assay
• Experiment for Drug Resistance: BrdUrd assay
• Mechanism Description: The RAS/RAF/MEk pathway is activated in more than 30% of human cancers, most commonly via mutation in the k-ras oncogene and also via mutations in BRAF. Importantly, in all cases the MEk-resistant cell lines retained their addiction to the mitogen-activated protein kinase (MAPk) pathway, as evidenced by their sensitivity to a selective inhibitor of the ERk1/2 kinases. These data suggest that tumors with acquired MEk inhibitor resistance remain dependent on the MAPk pathway and are therefore sensitive to inhibitors that act downstream of the mutated MEk target.

Investigative Drug(s) 2 drug(s) in total

BRAF/MEK inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Melanoma [6]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: BRAF/MEK inhibitors
• Molecule Alteration: Missense mutation; p.Q60P (c.179A>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter96 AQueous assay

MEK inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Melanoma [1]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: MEK inhibitors
• Molecule Alteration: Missense mutation; p.N126D (c.376A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Disease Class: Melanoma [1]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: MEK inhibitors
• Molecule Alteration: Missense mutation; p.V35M (c.103G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Disease Class: Melanoma [1]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: MEK inhibitors
• Molecule Alteration: Missense mutation; p.L46F (c.136C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Disease Class: Melanoma [1]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: MEK inhibitors
• Molecule Alteration: Missense mutation; p.C125S (c.373T>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Melanoma [ICD-11: 2C30]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Skin
• The Specified Disease: Melanoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.87E-01; Fold-change: 9.14E-01; Z-score: 6.10E-01

References

• Ref 1: The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014 Jan;4(1):94-109. doi: 10.1158/2159-8290.CD-13-0617. Epub 2013 Nov 21.
• Ref 2: Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat Commun. 2014 Dec 2;5:5694. doi: 10.1038/ncomms6694.
• Ref 3: Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. J Clin Invest. 2015 Apr;125(4):1459-70. doi: 10.1172/JCI78954. Epub 2015 Feb 23.
• Ref 4: BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014 Apr 1;20(7):1965-77. doi: 10.1158/1078-0432.CCR-13-3122. Epub 2014 Jan 24.
• Ref 5: ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol Cancer Ther. 2012 May;11(5):1143-54. doi: 10.1158/1535-7163.MCT-11-1010. Epub 2012 Mar 8.
• Ref 6: MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibitionCancer Discov. 2014 Jan;4(1):61-8. doi: 10.1158/2159-8290.CD-13-0631. Epub 2013 Nov 21.