Drug Information

Drug (ID: DG01739) and It's Reported Resistant Information
Name
Vemurafenib/Cobimetinib
Synonyms
Vemurafenib/Cobimetinib
    Click to Show/Hide
Drug Resistance Disease(s)
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Melanoma [ICD-11: 2C30]
[1]
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Melanoma [ICD-11: 2C30]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Mitogen-activated protein kinase (MAPK) [1]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Phosphorylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model WM1366 DT R cells melanoma Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 4-methylumbelliferyl heptanoate assay
Mechanism Description In summary, BRAFi/MEKi combinations inhibit proliferation and induce apoptosis in sensitive, but not in BRAFi/MEKi-resistant cells in 2D and 3D cell culture models. This effect may be partially caused by an upregulation of pERK and downregulation of mitochondrial apoptotic proteins in the resistant cells.
Key Molecule: COS-L protein [1]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model WM1366 DT R cells melanoma Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Flow cytometry; Transcriptome assay; qPCR
Experiment for
Drug Resistance		 4-methylumbelliferyl heptanoate assay
Mechanism Description Altogether, BRAFi/MEKi induce immune stimulatory molecules and APM components in sensitive NRAS-mutant melanoma cells, while the expression of these molecules is reversed in the resistant NRAS-mutant melanoma cells.
  Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: ATP-binding cassette sub-family C2 (ABCC2) [2]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Hs294T R cells Skin Homo sapiens (Human) CVCL_E3AI
Experiment for
Molecule Alteration		 Western blot assay; qRT-PCR
Experiment for
Drug Resistance		 XTT assay
Mechanism Description ABC transporters and CYP1A1 protein level was also upregulated in resistant cells. Moreover, the elevated levels of ABCA1, ABCC2 and ABCG2 were here shown for the first time in BRAFi/MEKi resistant cells.
Key Molecule: ATP-binding cassette sub-family C2 (ABCC2) [2]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model WM9 R cells melanoma Homo sapiens (Human) CVCL_E3AH
Experiment for
Molecule Alteration		 Western blot assay; qRT-PCR
Experiment for
Drug Resistance		 XTT assay
Mechanism Description ABC transporters and CYP1A1 protein level was also upregulated in resistant cells. Moreover, the elevated levels of ABCA1, ABCC2 and ABCG2 were here shown for the first time in BRAFi/MEKi resistant cells.
Key Molecule: ATP-binding cassette sub-family A1 (ABCA1) [2]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Hs294T R cells Skin Homo sapiens (Human) CVCL_E3AI
WM9 R cells melanoma Homo sapiens (Human) CVCL_E3AH
Experiment for
Molecule Alteration		 Western blot assay; qRT-PCR
Experiment for
Drug Resistance		 XTT assay
Mechanism Description ABC transporters and CYP1A1 protein level was also upregulated in resistant cells. Moreover, the elevated levels of ABCA1, ABCC2 and ABCG2 were here shown for the first time in BRAFi/MEKi resistant cells.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: AKT serine/threonine kinase (AKT) [2]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Phosphorylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K/AKT signaling pathway Activation hsa04151
MAPK signaling pathway Activation hsa04010
In Vitro Model Hs294T R cells Skin Homo sapiens (Human) CVCL_E3AI
WM9 R cells melanoma Homo sapiens (Human) CVCL_E3AH
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 XTT assay
Mechanism Description Obtained resistant melanoma cells exhibit increased activation of signaling pathways, including JNK, which raised activation in resistant to BRAFi/MEKi melanoma cells is demonstrated here for the first time.
Key Molecule: Mitogen-activated protein kinase 8 (MAPK8) [2]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Phosphorylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K/AKT signaling pathway Activation hsa04151
MAPK signaling pathway Activation hsa04010
In Vitro Model Hs294T R cells Skin Homo sapiens (Human) CVCL_E3AI
WM9 R cells melanoma Homo sapiens (Human) CVCL_E3AH
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 XTT assay
Mechanism Description Obtained resistant melanoma cells exhibit increased activation of signaling pathways, including JNK, which raised activation in resistant to BRAFi/MEKi melanoma cells is demonstrated here for the first time.
Key Molecule: Mitogen-activated protein kinase 12 (MAPK12) [2]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Phosphorylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K/AKT signaling pathway Activation hsa04151
MAPK signaling pathway Activation hsa04010
In Vitro Model Hs294T R cells Skin Homo sapiens (Human) CVCL_E3AI
WM9 R cells melanoma Homo sapiens (Human) CVCL_E3AH
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 XTT assay
Mechanism Description Obtained resistant melanoma cells exhibit increased activation of signaling pathways, including JNK, which raised activation in resistant to BRAFi/MEKi melanoma cells is demonstrated here for the first time.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [4]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [5]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.V600X (c.1798_1799)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.V600K (c.1798_1799delGTinsAA)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
References
Ref 1 BRAF and MEK inhibitor combinations induce potent molecular and immunological effects in NRAS-mutant melanoma cells: Insights into mode of action and resistance mechanisms. Int J Cancer. 2024 Mar 15;154(6):1057-1072.
Ref 2 Characterization of two melanoma cell lines resistant to BRAF/MEK inhibitors (vemurafenib and cobimetinib). Cell Commun Signal. 2024 Aug 23;22(1):410.
Ref 3 Improved survival with MEK inhibition in BRAF-mutated melanomaN Engl J Med. 2012 Jul 12;367(2):107-14. doi: 10.1056/NEJMoa1203421. Epub 2012 Jun 4.
Ref 4 U.S. Food and Drug Administration.
Ref 5 Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b studyLancet Oncol. 2014 Aug;15(9):954-65. doi: 10.1016/S1470-2045(14)70301-8. Epub 2014 Jul 15.

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