Drug Information

Drug (ID: DG01879) and It's Reported Resistant Information

• Name: MEK inhibitors
• Synonyms: MEK inhibitors
• Indication:
  In total 4 Indication(s)
  Melanoma [ICD-11: 2C30]; Approved; [1]
  Thyroid cancer [ICD-11: 2D10]; Phase 3; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 1/2; [1]
  Non-small-cell lung cancer [ICD-11: 2C25]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Melanoma [ICD-11: 2C30]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Melanoma [ICD-11: 2C30]; [3]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [3]
• Target: MAPK/ERK kinase kinase (MAP3K); NOUNIPROTAC; [1]

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D67N (c.199G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.D67N (c.199G>A) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.I99T (c.296T>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.I99T (c.296T>C) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.I103N (c.308T>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.I103N (c.308T>A) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.K104N (c.312A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.K104N (c.312A>C) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.I111N (c.332T>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.I111N (c.332T>A) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.L115P (c.344T>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.L115P (c.344T>C) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.H119P (c.356A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.H119P (c.356A>C) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.E120D (c.360G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.E120D (c.360G>C) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.G128D (c.383G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.G128D (c.383G>A) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.F129L (c.385T>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.F129L (c.385T>C) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.F133L (c.397T>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.F133L (c.397T>C) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.V211D (c.632T>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.V211D (c.632T>A) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.L215P (c.644T>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.L215P (c.644T>C) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase KRas (KRAS) [4]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.G12 (c.34_36)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CellTiter 96 Aqueous One assay
• Mechanism Description: The missense mutation p.G12 (c.34_36) in gene KRAS cause the sensitivity of MEK inhibitors by unusual activation of pro-survival pathway

Melanoma [ICD-11: 2C30]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.P124L (c.371C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The missense mutation p.P124L (c.371C>T) in gene MAP2K1 cause the resistance of MEK inhibitors by aberration of the drug's therapeutic target

Key Molecule: MAPK/ERK kinase 2 (MEK2) [2]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• 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 blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: MAPK/ERK kinase 2 (MEK2) [2]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• 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 blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: MAPK/ERK kinase 2 (MEK2) [2]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• 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 blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: MAPK/ERK kinase 2 (MEK2) [2]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• 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 blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [5]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.C121S (c.361T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.70 Å; PDB: 7B7R
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.01 Å; PDB: 7F2X

RMSD: 2.36; TM score: 0.87257; Amino acid change: C121S

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Human melanoma tissue; N.A.
• Mechanism Description: The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the resistance of MEK inhibitors by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [6]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.K57N (c.171G>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; N.A.
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.K57N (c.171G>C) in gene MAP2K1 cause the resistance of MEK inhibitors by unusual activation of pro-survival pathway

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.L597R (c.1790T>G)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [7]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.D594A (c.1781A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.D594A (c.1781A>C) in gene BRAF cause the sensitivity of MEK inhibitors by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [7]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.K483M (c.1448_1449delAAinsTG)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.K483M (c.1448_1449delAAinsTG) in gene BRAF cause the sensitivity of MEK inhibitors by unusual activation of pro-survival pathway

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [8]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.K601R (c.1802A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; N.A.
• Mechanism Description: The missense mutation p.K601R (c.1802A>G) in gene BRAF cause the sensitivity of MEK inhibitors by unusual activation of pro-survival pathway

Ovarian cancer [ICD-11: 2C73]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [9]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: IF-deletion; p.Q56_V60delQKQKV (c.166_180del15)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Whole transcriptome analysis
• Experiment for Drug Resistance: Colony formation assay

References

• Ref 1: Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trialLancet Oncol. 2012 Aug;13(8):782-9. doi: 10.1016/S1470-2045(12)70269-3. Epub 2012 Jul 16.
• Ref 2: 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 3: MEK1 mutations confer resistance to MEK and B-RAF inhibitionProc Natl Acad Sci U S A. 2009 Dec 1;106(48):20411-6. doi: 10.1073/pnas.0905833106. Epub 2009 Nov 13.
• Ref 4: Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemiaCancer Res. 2008 Aug 15;68(16):6803-9. doi: 10.1158/0008-5472.CAN-08-0101.
• Ref 5: Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profilingJ Clin Oncol. 2011 Aug 1;29(22):3085-96. doi: 10.1200/JCO.2010.33.2312. Epub 2011 Mar 7.
• Ref 6: Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanomaClin Cancer Res. 2013 Apr 15;19(8):2257-64. doi: 10.1158/1078-0432.CCR-12-3476. Epub 2013 Feb 26.
• Ref 7: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAFCell. 2010 Jan 22;140(2):209-21. doi: 10.1016/j.cell.2009.12.040.
• Ref 8: Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitorJ Clin Oncol. 2013 Feb 1;31(4):482-9. doi: 10.1200/JCO.2012.43.5966. Epub 2012 Dec 17.
• Ref 9: Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian CancerJ Clin Oncol. 2015 Dec 1;33(34):4099-105. doi: 10.1200/JCO.2015.62.4726. Epub 2015 Aug 31.