Disease Information

General Information of the Disease (ID: DIS00080)
Name
Melanoma
ICD
ICD-11: 2C30
Resistance Map
Type(s) of Resistant Mechanism of This Disease
  ADTT: Aberration of the Drug's Therapeutic Target
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  MRAP: Metabolic Reprogramming via Altered Pathways
  RTDM: Regulation by the Disease Microenvironment
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
18 drug(s) in total
Click to Show/Hide the Full List of Drugs
Dabrafenib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Myeloma cell metalloproteinase (ADAM9) [1]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 2.42E-01
Fold-change: 9.18E-02
Z-score: 1.20E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A.
Key Molecule: GTPase Nras (NRAS) [17], [18], [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61K
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
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-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
-
F
-
Q
0
|
S
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
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G
G
A
A
G
G
G
G
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V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
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C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
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F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
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I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
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A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; Sanger sequencing assay; Next generation assay; Single PCR-based analysis
Experiment for
Drug Resistance		 Progression-free and post-progression survival asaay; Computed tomography assay; Positron emission tomography assay
Mechanism Description Another post-relapse tumor harbored an acquired NRASQ61k missense mutation together with focal BRAF amplification. The resistant tumor from a third patient harbored both a MEk2 mutation and BRAF amplification. Resistance mechanisms are identified in 9/11 progressing tumours and MAPk reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEk2. Our data confirming that MEk2C125S, but not the synonymous MEk1C121S protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEk2 mutations in combination therapy-resistant melanomas.
Key Molecule: GTPase Nras (NRAS) [19], [20]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61R
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.24  Å
PDB: 7F68
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.46
TM score: 0.94384
Amino acid change:
Q61R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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0
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S
-
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E
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K
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L
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V
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V
V
10
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G
G
A
A
G
G
G
G
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V
G
G
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K
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S
A
A
L
L
20
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T
T
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I
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Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
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D
D
E
E
Y
Y
D
D
P
P
T
T
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I
E
E
D
D
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S
40
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Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
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T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
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G
G
Q
R
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
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Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
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C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
D
90
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F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
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R
E
E
Q
Q
100
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I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
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P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
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L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
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A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
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Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
-
L
-
N
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next generation assay; Single PCR-based analysis
Experiment for
Drug Resistance		 Computed tomography assay; Positron emission tomography assay; Progression-free and overall survival assay
Mechanism Description NRAS mutations (Q61R and Q61k in codon 61) were detected in two of ten patients (20%). Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: GTPase KRas (KRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.31  Å
PDB: 6T5V
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6MNX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.14
TM score: 0.96411
Amino acid change:
Q61H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
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G
G
A
A
C
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
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T
T
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I
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Q
L
L
I
I
Q
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N
N
H
H
F
F
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V
30
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D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
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I
D
D
G
G
E
E
50
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T
T
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C
L
L
L
L
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D
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I
L
L
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D
T
T
A
A
60
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G
G
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H
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
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Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
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L
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
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F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
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I
I
K
K
R
R
V
V
K
K
D
D
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S
E
E
D
D
V
V
110
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P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
C
D
D
120
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L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
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A
A
Q
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D
D
L
L
A
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R
R
S
S
Y
Y
G
G
I
I
140
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P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
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Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vitro Model Melanoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.
Key Molecule: GTPase KRas (KRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12R
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.50  Å
PDB: 6CU6
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.17
TM score: 0.95613
Amino acid change:
G12R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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0
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G
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
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G
G
A
A
G
R
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
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T
T
I
I
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L
L
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I
Q
Q
N
N
H
H
F
F
V
V
30
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D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
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Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
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T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
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G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
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Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
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C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
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F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
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E
E
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Q
100
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I
I
K
K
R
R
V
V
K
K
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D
S
S
E
E
D
D
V
V
110
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P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
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L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
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A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
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P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
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Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
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V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vitro Model Melanoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.
Key Molecule: GTPase Nras (NRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12R
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.50  Å
PDB: 6CU6
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.17
TM score: 0.95613
Amino acid change:
G12R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
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G
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
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G
G
A
A
G
R
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
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T
T
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I
Q
Q
L
L
I
I
Q
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N
N
H
H
F
F
V
V
30
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D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
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Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
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Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
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C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
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F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
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I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
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A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
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P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
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Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
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V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: GTPase KRas (KRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12C
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.60  Å
PDB: 8JGD
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.93157
Amino acid change:
G12C
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
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G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
C
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vitro Model Melanoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.
Key Molecule: GTPase Nras (NRAS) [19], [21]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 8JHL
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.9318
Amino acid change:
G12D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
D
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy. 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.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [17]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.N126D
 Molecule Info 
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.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [17]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.L46F
 Molecule Info 
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.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [21]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.C125S
 Molecule Info 
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.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [22]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q60P
 Molecule Info 
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.
Key Molecule: GTPase Nras (NRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61L
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: GTPase Nras (NRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G13R
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [21]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.E207K
 Molecule Info 
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.
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: Vascular endothelial growth factor A (VEGFA) [1]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 3.08E-01
Fold-change: 2.71E-02
Z-score: 1.03E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A.
Key Molecule: hsa-miR-126-3p [1]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A.
Tryptophan
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [2]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Tryptophan
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 3.72E-01
Fold-change: 3.27E-02
Z-score: 9.09E-01
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation MAPK/RAS signaling pathway Activation hsa04010
In Vivo Model VillinCreErt2 and VillinCreErt2 APCfl/fl KRASG12D/+ C57BL/6J mouse model Mus musculus
Experiment for
Molecule Alteration		 Amino acid mass spectrometry assay
Experiment for
Drug Resistance		 Flow cytometry (SIINFEKL assays); T cell killing assay and clonogenic assay
Mechanism Description Sloppiness is defined by ribosomal frameshifting upon tryptophan shortage. MAPK pathway hyperactivation links sloppiness to cancer. Drug-resistant cancer cells remain sloppy and are targeted by T cells.
Key Molecule: Ras-specific guanine nucleotide-releasing factor 2 (RGRF2) [2]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Tryptophan
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation MAPK/RAS signaling pathway Activation hsa04010
In Vivo Model VillinCreErt2 and VillinCreErt2 APCfl/fl KRASG12D/+ C57BL/6J mouse model Mus musculus
Experiment for
Molecule Alteration		 Amino acid mass spectrometry assay
Experiment for
Drug Resistance		 Flow cytometry (SIINFEKL assays); T cell killing assay and clonogenic assay
Mechanism Description Sloppiness is defined by ribosomal frameshifting upon tryptophan shortage. MAPK pathway hyperactivation links sloppiness to cancer. Drug-resistant cancer cells remain sloppy and are targeted by T cells.
Cisplatin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [4]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 8.38E-01
Fold-change: 1.02E-02
Z-score: 2.07E-01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell viability Activation hsa05200
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Overexpressed 211 could enhance the anticancer effect of cisplatin and restoration of miR-211 rendered susceptibility to cisplatin in cisplatin-resistant cells.miR-211 could be transcriptionally repressed by EZH2 mediated promoter methylation.
Key Molecule: Phosphatase and tensin homolog (PTEN) [8]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 2.31E-01
Fold-change: -3.56E-02
Z-score: -1.22E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/FAKT signaling pathway Activation hsa04151
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
SkMEL1 cells Skin Homo sapiens (Human) CVCL_0068
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Colony formation assay; Annexin V-fluorescein isothiocyanate (FITC) apoptosis analysis; Wound scratch healing or transwell invasion assay
Mechanism Description PTEN can interact with AkT and FAk and inhibit their activity through their dephosphorylation, Akt and FAk signaling pathways are involved in miR301a/PTEN-promoting malignant phenotypes in MM cells, miR301a promotes MM progression via activation of Akt and FAk signaling pathways by down regulating PTEN.
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [15]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation AKT/P53 signaling pathway Regulation N.A.
Cell viability Activation hsa05200
In Vitro Model M8 cells Skin Homo sapiens (Human) N.A.
Sk-Mel-19 cells Skin Homo sapiens (Human) CVCL_6025
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description miR-30a-5p was over-expressed in cisplatin resistant melanoma cells and could influence the activity of PI3k/AkT and the protein level of P53 by targeting IGF1R gene.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-301 [8]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/FAKT signaling pathway Activation hsa04151
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
SkMEL1 cells Skin Homo sapiens (Human) CVCL_0068
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Colony formation assay; Annexin V-fluorescein isothiocyanate (FITC) apoptosis analysis; Wound scratch healing or transwell invasion assay
Mechanism Description PTEN can interact with AkT and FAk and inhibit their activity through their dephosphorylation, Akt and FAk signaling pathways are involved in miR301a/PTEN-promoting malignant phenotypes in MM cells, miR301a promotes MM progression via activation of Akt and FAk signaling pathways by down regulating PTEN.
Key Molecule: hsa-mir-211 [4]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Methylation
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell viability Activation hsa05200
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Overexpressed 211 could enhance the anticancer effect of cisplatin and restoration of miR-211 rendered susceptibility to cisplatin in cisplatin-resistant cells.miR-211 could be transcriptionally repressed by EZH2 mediated promoter methylation.
Key Molecule: hsa-miR-30a-5p [15]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation AKT/P53 signaling pathway Regulation N.A.
Cell viability Activation hsa05200
In Vitro Model M8 cells Skin Homo sapiens (Human) N.A.
Sk-Mel-19 cells Skin Homo sapiens (Human) CVCL_6025
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description miR-30a-5p was over-expressed in cisplatin resistant melanoma cells and could influence the activity of PI3k/AkT and the protein level of P53 by targeting IGF1R gene.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-488-3p [16]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
B16 cells Skin Homo sapiens (Human) CVCL_F936
HEMn-LP cells Skin Homo sapiens (Human) N.A.
WM451 cells Skin Homo sapiens (Human) CVCL_6357
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometric analysis
Mechanism Description microRNA-488-3p sensitizes malignant melanoma cells to cisplatin by targeting PRkDC.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: DNA-dependent catalytic protein kinase (PRKDC) [16]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
B16 cells Skin Homo sapiens (Human) CVCL_F936
HEMn-LP cells Skin Homo sapiens (Human) N.A.
WM451 cells Skin Homo sapiens (Human) CVCL_6357
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometric analysis
Mechanism Description microRNA-488-3p sensitizes malignant melanoma cells to cisplatin by targeting PRkDC.
Paclitaxel
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Histone deacetylase 3 (HDAC3) [5]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Paclitaxel
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 4.19E-01
Fold-change: -1.04E-02
Z-score: -8.20E-01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
In Vitro Model SNU387 cells Liver Homo sapiens (Human) CVCL_0250
Malme3M cells Skin Homo sapiens (Human) CVCL_1438
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-326 [5]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Paclitaxel
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
In Vitro Model SNU387 cells Liver Homo sapiens (Human) CVCL_0250
Malme3M cells Skin Homo sapiens (Human) CVCL_1438
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [12]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Paclitaxel
 Drug Info 
Molecule Alteration Methylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model B16-BL6 cells Skin Homo sapiens (Human) CVCL_0157
Colon-26 carcinoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 WST-8 assay
Mechanism Description These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-335 [5], [29]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Paclitaxel
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
miR335/SIAH2/HDAC3 signaling pathway Regulation N.A.
In Vitro Model Malme3M cells Skin Homo sapiens (Human) CVCL_1438
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Trypan blue exclusion assay; Transwell assay
Mechanism Description miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.
Key Molecule: hsa-mir-217 [5]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Paclitaxel
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
In Vitro Model SNU387 cells Liver Homo sapiens (Human) CVCL_0250
Malme3M cells Skin Homo sapiens (Human) CVCL_1438
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: hsa-mir-200b [5]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Paclitaxel
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model SNU387 cells Liver Homo sapiens (Human) CVCL_0250
Malme3M cells Skin Homo sapiens (Human) CVCL_1438
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.
Key Molecule: hsa-miR-326 [5]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Paclitaxel
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
In Vitro Model SNU387 cells Liver Homo sapiens (Human) CVCL_0250
Malme3M cells Skin Homo sapiens (Human) CVCL_1438
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-326, which forms a negative feedback regulatory loop with HDAC3, regulates the invasion and the metastatic potential of cancer cells and tumor-induced angiogenesis in response to anti-cancer drugs. miR-200b, miR-217, and miR-335, which form a positive feedback loop with HDAC3, confer sensitivity to anti-cancer drugs. We show that CAGE, reported to form a feedback loop with miR-200b, serves as a downstream target of HDAC3 and miR-326. In this study, we show that the regulation of the miR-326/HDAC3 axis can be employed for the development of anti-cancer therapeutics.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: E3 ubiquitin-protein ligase SIAH2 (SIAH2) [29]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Paclitaxel
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
miR335/SIAH2/HDAC3 signaling pathway Regulation N.A.
In Vitro Model Malme3M cells Skin Homo sapiens (Human) CVCL_1438
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Trypan blue exclusion assay; Transwell assay
Mechanism Description miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.
Vemurafenib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: RAF proto-oncogene serine/threonine-protein kinase (RAF1) [6]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 4.47E-01
Fold-change: -1.48E-02
Z-score: -7.72E-01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
MAPK/PI3K/AKT signaling pathway Inhibition hsa05235
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Mel-CV cells Skin Homo sapiens (Human) CVCL_S996
Experiment for
Molecule Alteration		 Immunohistochemical staining assay; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-7 expression was decreased in both VemR A375 and Mel-CVR melanoma cells and its low expression contributed to BRAFi resistance. Furthermore, by decreasing the expression levels of EGFR, IGF-1R and CRAF, miR-7 could inhibit the activation of RAS/RAF/MEk/ERk (MAPk) and PI3k/AkT pathway and partially reverse the resistance to BRAFi in VemR A375 melanoma cells.
Key Molecule: Epidermal growth factor receptor (EGFR) [6]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.60E-01
Fold-change: -9.63E-02
Z-score: -1.44E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
MAPK/PI3K/AKT signaling pathway Inhibition hsa05235
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Mel-CV cells Skin Homo sapiens (Human) CVCL_S996
Experiment for
Molecule Alteration		 Immunohistochemical staining assay; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-7 expression was decreased in both VemR A375 and Mel-CVR melanoma cells and its low expression contributed to BRAFi resistance. Furthermore, by decreasing the expression levels of EGFR, IGF-1R and CRAF, miR-7 could inhibit the activation of RAS/RAF/MEk/ERk (MAPk) and PI3k/AkT pathway and partially reverse the resistance to BRAFi in VemR A375 melanoma cells.
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [6]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
MAPK/PI3K/AKT signaling pathway Inhibition hsa05235
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Mel-CV cells Skin Homo sapiens (Human) CVCL_S996
Experiment for
Molecule Alteration		 Immunohistochemical staining assay; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-7 expression was decreased in both VemR A375 and Mel-CVR melanoma cells and its low expression contributed to BRAFi resistance. Furthermore, by decreasing the expression levels of EGFR, IGF-1R and CRAF, miR-7 could inhibit the activation of RAS/RAF/MEk/ERk (MAPk) and PI3k/AkT pathway and partially reverse the resistance to BRAFi in VemR A375 melanoma cells.
Key Molecule: Monocyte chemotactic and activating factor (CCL2) [48]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
In Vitro Model PLX4032-resistant cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description CCL2 and miR-125b, miR-34a and miR-100 are potential targets for overcoming the miR-34a and miR-100 are potential targets for overcoming the resistance to BRAFi in melanoma.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: UV radiation resistance-associated gene protein (UVRAG) [7]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 4.69E-01
Fold-change: -2.07E-02
Z-score: -7.33E-01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell autophagy Inhibition hsa04140
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
A375-R cells Skin Homo sapiens (Human) CVCL_6234
G-361 cells Skin Homo sapiens (Human) CVCL_1220
G361/R cells Skin Homo sapiens (Human) CVCL_IW13
MeWo cells Skin Homo sapiens (Human) CVCL_0445
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometric analysis
Mechanism Description miR216b enhances the efficacy of vemurafenib by targeting Beclin-1, UVRAG and ATG5 in melanoma. miR216b suppresses autophagy in both BRAFi-sensitive and -resistant melanoma cells.
Key Molecule: Autophagy protein 5 (ATG5) [7]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.48E-01
Fold-change: -3.74E-02
Z-score: -1.49E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell autophagy Inhibition hsa04140
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
A375-R cells Skin Homo sapiens (Human) CVCL_6234
G-361 cells Skin Homo sapiens (Human) CVCL_1220
G361/R cells Skin Homo sapiens (Human) CVCL_IW13
MeWo cells Skin Homo sapiens (Human) CVCL_0445
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometric analysis
Mechanism Description miR216b enhances the efficacy of vemurafenib by targeting Beclin-1, UVRAG and ATG5 in melanoma. miR216b suppresses autophagy in both BRAFi-sensitive and -resistant melanoma cells.
Key Molecule: Beclin-1 (BECN1) [7]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell autophagy Inhibition hsa04140
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
A375-R cells Skin Homo sapiens (Human) CVCL_6234
G-361 cells Skin Homo sapiens (Human) CVCL_1220
G361/R cells Skin Homo sapiens (Human) CVCL_IW13
MeWo cells Skin Homo sapiens (Human) CVCL_0445
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometric analysis
Mechanism Description miR216b enhances the efficacy of vemurafenib by targeting Beclin-1, UVRAG and ATG5 in melanoma. miR216b suppresses autophagy in both BRAFi-sensitive and -resistant melanoma cells.
Key Molecule: hsa-mir-216b [7]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell autophagy Inhibition hsa04140
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
A375-R cells Skin Homo sapiens (Human) CVCL_6234
G-361 cells Skin Homo sapiens (Human) CVCL_1220
G361/R cells Skin Homo sapiens (Human) CVCL_IW13
MeWo cells Skin Homo sapiens (Human) CVCL_0445
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometric analysis
Mechanism Description miR216b enhances the efficacy of vemurafenib by targeting Beclin-1, UVRAG and ATG5 in melanoma. miR216b suppresses autophagy in both BRAFi-sensitive and -resistant melanoma cells.
Key Molecule: hsa-mir-7 [6]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
MAPK/PI3K/AKT signaling pathway Inhibition hsa05235
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Mel-CV cells Skin Homo sapiens (Human) CVCL_S996
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-7 expression was decreased in both VemR A375 and Mel-CVR melanoma cells and its low expression contributed to BRAFi resistance. Furthermore, by decreasing the expression levels of EGFR, IGF-1R and CRAF, miR-7 could inhibit the activation of RAS/RAF/MEk/ERk (MAPk) and PI3k/AkT pathway and partially reverse the resistance to BRAFi in VemR A375 melanoma cells.
Key Molecule: hsa-mir-100 [48]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
In Vitro Model PLX4032-resistant cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description CCL2 and miR-125b, miR-34a and miR-100 are potential targets for overcoming the miR-34a and miR-100 are potential targets for overcoming the resistance to BRAFi in melanoma.
Key Molecule: hsa-mir-125b [48]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
In Vitro Model PLX4032-resistant cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description CCL2 and miR-125b, miR-34a and miR-100 are potential targets for overcoming the miR-34a and miR-100 are potential targets for overcoming the resistance to BRAFi in melanoma.
Key Molecule: hsa-mir-34 [48]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
In Vitro Model PLX4032-resistant cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description CCL2 and miR-125b, miR-34a and miR-100 are potential targets for overcoming the miR-34a and miR-100 are potential targets for overcoming the resistance to BRAFi in melanoma.
Drug Resistance 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) [40]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Structural variation
Copy number gain
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Multivariate analysis of overall or disease-free survival assay
Mechanism Description Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-204-5p [41]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation ERK1/2/MEK activation signaling pathway|hsa04210) Regulation N.A.
MAPK signaling pathway Activation hsa04010
PI3K signaling pathway Activation hsa04151
RAS signaling pathway Activation hsa04014
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR204-5p and miR211-5p contribute to BRAF inhibitor resistance in melanoma. MTT assays revealed a moderate but consistent increase in resistance to VMF in cells overexpressing miR211-5p or miR204-5p. Joint overexpression of miR204-5p and miR211-5p durably stimulated Ras and MAPk upregulation. Resistance to BRAFi in melanoma involves genetic alterations that lead to reactivation of the MAPk pathway or activation of PI3-k/AkT signalling.
Key Molecule: hsa-miR-211-5p [41]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation ERK1/2/MEK activation signaling pathway|hsa04210) Regulation N.A.
MAPK signaling pathway Activation hsa04010
PI3K signaling pathway Activation hsa04151
RAS signaling pathway Activation hsa04014
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR204-5p and miR211-5p contribute to BRAF inhibitor resistance in melanoma. MTT assays revealed a moderate but consistent increase in resistance to VMF in cells overexpressing miR211-5p or miR204-5p. Joint overexpression of miR204-5p and miR211-5p durably stimulated Ras and MAPk upregulation. Resistance to BRAFi in melanoma involves genetic alterations that lead to reactivation of the MAPk pathway or activation of PI3-k/AkT signalling.
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Microphthalmia-associated transcription factor (MITF) [42]
Metabolic Type Glucose metabolism
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model Melanoma patients Homo Sapiens
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cell prognosis assay
Mechanism Description Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.
Key Molecule: Adenosylmethionine decarboxylase 1 (AMD1) [43]
Metabolic Type Glucose metabolism
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK 293T cells Kidney Homo sapiens (Human) CVCL_0063
Hs294T cells Skin Homo sapiens (Human) CVCL_0331
SK-MEL-28 cells Skin Homo sapiens (Human) CVCL_0526
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reduces vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro cell line models and in vivo in a xenograft model. Polyamine biosynthesis signature is associated with poor prognosis and shorter progression free survival after BRAF/MAPK inhibitor treatment in melanoma cohorts, highlighting the clinical relevance of our findings.
Key Molecule: Microphthalmia-associated transcription factor (MITF) [42]
Metabolic Type Glucose metabolism
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model SK-MEL-28 cells Skin Homo sapiens (Human) CVCL_0526
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Microfluidic cdra chip assay
Mechanism Description Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.
Key Molecule: Microphthalmia-associated transcription factor (MITF) [42]
Metabolic Type Glucose metabolism
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Microfluidic cdra chip assay
Mechanism Description Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [17], [19], [44]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61K
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
|
-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
-
F
-
Q
0
|
S
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vitro Model M229 cells Skin Homo sapiens (Human) CVCL_D748
M238 cells Skin Homo sapiens (Human) CVCL_D751
M249 cells Skin Homo sapiens (Human) CVCL_D755
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: GTPase Nras (NRAS) [45], [40]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61K
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
|
-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
-
F
-
Q
0
|
S
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Liquid biopsy assay; Next-generation sequencing assay; Circulating-free DNA assay; Digital PCR assay
Experiment for
Drug Resistance		 Overall and disease-free assay
Mechanism Description Overexpression of PDGFRbeta or N-RAS(Q61k) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines.
Key Molecule: GTPase Nras (NRAS) [46]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61K
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
|
-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
-
F
-
Q
0
|
S
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Activation hsa04010
Mechanism Description BRAFV600E inhibition via vemurafenib induces paradoxical activation of MAPK through increased CRAF activity and acquired NRAS mutation. Moreover, mutations in genes upstream of RAF, such as the activating N-RASQ61K mutation, allow for BRAFV600 melanomas to escape molecular targeting.
Key Molecule: GTPase Nras (NRAS) [46]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61K
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
|
-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
-
F
-
Q
0
|
S
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Activation hsa04010
Mechanism Description BRAFV600E inhibition via vemurafenib induces paradoxical activation of MAPK through increased CRAF activity and acquired NRAS mutation. Moreover, mutations in genes upstream of RAF, such as the activating N-RASQ61K mutation, allow for BRAFV600 melanomas to escape molecular targeting.
Key Molecule: GTPase Nras (NRAS) [17], [19], [44]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61R
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.24  Å
PDB: 7F68
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.46
TM score: 0.94384
Amino acid change:
Q61R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
S
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
R
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
D
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
-
L
-
N
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vitro Model M229 cells Skin Homo sapiens (Human) CVCL_D748
M238 cells Skin Homo sapiens (Human) CVCL_D751
M249 cells Skin Homo sapiens (Human) CVCL_D755
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: GTPase KRas (KRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.31  Å
PDB: 6T5V
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6MNX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.14
TM score: 0.96411
Amino acid change:
Q61H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
C
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
S
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
H
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
L
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vitro Model Melanoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.
Key Molecule: GTPase Nras (NRAS) [17]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.31  Å
PDB: 6T5V
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6MNX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.14
TM score: 0.96411
Amino acid change:
Q61H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
C
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
S
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
H
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
L
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
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 In contrast, NRAS mutations and BRAF amplifications may still prove responsive to subsequent MEk inhibitor-based regimens, although the existing clinical data suggests that patients who progress following single-agent RAF inhibition are less likely to benefit from MEk inhibitors.
Key Molecule: GTPase KRas (KRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12R
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.50  Å
PDB: 6CU6
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.17
TM score: 0.95613
Amino acid change:
G12R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
R
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vitro Model Melanoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.
Key Molecule: GTPase Nras (NRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12R
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.50  Å
PDB: 6CU6
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.17
TM score: 0.95613
Amino acid change:
G12R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
R
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: GTPase KRas (KRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12C
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.60  Å
PDB: 8JGD
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.93157
Amino acid change:
G12C
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
C
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vitro Model Melanoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.
Key Molecule: GTPase Nras (NRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 8JHL
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.9318
Amino acid change:
G12D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
D
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [41]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation ERK1/2/MEK activation signaling pathway|hsa04210) Regulation N.A.
MAPK signaling pathway Activation hsa04010
PI3K signaling pathway Activation hsa04151
RAS signaling pathway Activation hsa04014
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Experiment for
Molecule Alteration		 Western blot analysis; GTPase assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR204-5p and miR211-5p contribute to BRAF inhibitor resistance in melanoma. MTT assays revealed a moderate but consistent increase in resistance to VMF in cells overexpressing miR211-5p or miR204-5p. Joint overexpression of miR204-5p and miR211-5p durably stimulated Ras and MAPk upregulation. Resistance to BRAFi in melanoma involves genetic alterations that lead to reactivation of the MAPk pathway or activation of PI3-k/AkT signalling.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [18]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.F57C
 Molecule Info 
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.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [17]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V35M
 Molecule Info 
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.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [17]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.C125S
 Molecule Info 
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.
Key Molecule: PI3-kinase alpha (PIK3CA) [47]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.E545K
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Computerized tomography assay
Mechanism Description In patient #11, sequential biopsies showed three mutations that were not detected in the pretreatment biopsy, including an activating mutation in PIk3CA E545k readily explaining the resistance.
Key Molecule: Phosphatase and tensin homolog (PTEN) [22]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.R159S
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation PI3K signaling pathway Activation hsa04151
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.
Key Molecule: GTPase Nras (NRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61L
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: GTPase Nras (NRAS) [19]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G13R
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Temozolomide
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: L-glutamine amidohydrolase (GLS) [9]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Temozolomide
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 5.27E-01
Fold-change: -3.92E-02
Z-score: -6.41E-01
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HT144 cells Skin Homo sapiens (Human) CVCL_0318
SkMEL5 cells Skin Homo sapiens (Human) CVCL_0527
Experiment for
Molecule Alteration		 Dual luciferase reporter assay; Western blot analysis; Immunohistochemistry assays
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Overexpression of miR203 sensitizes MM cells to TMZ by targeting GLS.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-203 [9]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Temozolomide
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HT144 cells Skin Homo sapiens (Human) CVCL_0318
SkMEL5 cells Skin Homo sapiens (Human) CVCL_0527
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Overexpression of miR203 sensitizes MM cells to TMZ by targeting GLS.
Etoposide
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Programmed cell death protein 4 (PDCD4) [10]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Etoposide
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 6.26E-02
Fold-change: -1.06E-01
Z-score: -1.95E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
U251 cells Brain Homo sapiens (Human) CVCL_0021
HEK293T cells Kidney Homo sapiens (Human) CVCL_0063
PARP cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-424 [10]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Etoposide
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
U251 cells Brain Homo sapiens (Human) CVCL_0021
HEK293T cells Kidney Homo sapiens (Human) CVCL_0063
PARP cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.
Binimetinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [13]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Binimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61K (c.181C>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
|
-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
-
F
-
Q
0
|
S
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Cutaneous melanoma tissue N.A.
Mechanism Description The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway
Key Molecule: GTPase Nras (NRAS) [13]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Binimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61R (c.182A>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.24  Å
PDB: 7F68
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.46
TM score: 0.94384
Amino acid change:
Q61R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
S
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
R
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
D
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
-
L
-
N
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Cutaneous melanoma tissue N.A.
Mechanism Description The missense mutation p.Q61R (c.182A>G) in gene NRAS cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway
Key Molecule: GTPase Nras (NRAS) [13]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Binimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61R (c.182A>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.24  Å
PDB: 7F68
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.46
TM score: 0.94384
Amino acid change:
Q61R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
S
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
R
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
D
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
-
L
-
N
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Cutaneous melanoma tissue N.A.
Mechanism Description The missense mutation p.Q61R (c.182A>G) in gene NRAS cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [13]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Binimetinib
 Drug 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
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Cutaneous melanoma tissue N.A.
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Binimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.L597S (c.1789_1790delCTinsTC)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vitro Model Skin sample N.A.
In Vivo Model Mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Crystal violet staining assay
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [13]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Binimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600X (c.1798_1800)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Cutaneous melanoma tissue N.A.
Mechanism Description The missense mutation p.V600X (c.1798_1800) in gene BRAF cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway
Key Molecule: GTPase Nras (NRAS) [13]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Binimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61L (c.182A>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Cutaneous melanoma tissue N.A.
Mechanism Description The missense mutation p.Q61L (c.182A>T) in gene NRAS cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway
Key Molecule: GTPase Nras (NRAS) [13]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Binimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61L (c.182A>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Cutaneous melanoma tissue N.A.
Mechanism Description The missense mutation p.Q61L (c.182A>T) in gene NRAS cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway
Dabrafenib/Trametinib
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) [11]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib/Trametinib
 Drug Info 
Molecule Alteration Phosphorylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model WM1366 VC 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 [11]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Dabrafenib/Trametinib
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model WM1366 VC 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.
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) [23]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Dabrafenib/Trametinib
 Drug 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
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [24]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Dabrafenib/Trametinib
 Drug 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
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [24]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Dabrafenib/Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600K (c.1798_1799delGTinsAA)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [25]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Dabrafenib/Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600X (c.1798_1799)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [26]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Dabrafenib/Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600X (c.1798_1800)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
Dacarbazine
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-31 [27]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Dacarbazine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell colony Inhibition hsa05200
Cell proliferation Inhibition hsa05200
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
293T cells Breast Homo sapiens (Human) CVCL_0063
HT144 cells Skin Homo sapiens (Human) CVCL_0318
SkMEL5 cells Skin Homo sapiens (Human) CVCL_0527
SkMEL1 cells Skin Homo sapiens (Human) CVCL_0068
A2058 cells Skin Homo sapiens (Human) CVCL_1059
A875 cells Skin Homo sapiens (Human) CVCL_4733
M21 cells Skin Homo sapiens (Human) CVCL_D031
SkMEL13 cells Skin Homo sapiens (Human) CVCL_6022
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description miR-31 could suppress tumor growth and enhance sensitivity to dacarbazine (DTIC) by down-regulating SOX10 mainly via inhibiting PI3k/AkT signaling pathway in melanoma.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Transcription factor SOX-10 (SOX10) [27]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Dacarbazine
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell colony Inhibition hsa05200
Cell proliferation Inhibition hsa05200
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
293T cells Breast Homo sapiens (Human) CVCL_0063
HT144 cells Skin Homo sapiens (Human) CVCL_0318
SkMEL5 cells Skin Homo sapiens (Human) CVCL_0527
SkMEL1 cells Skin Homo sapiens (Human) CVCL_0068
A2058 cells Skin Homo sapiens (Human) CVCL_1059
A875 cells Skin Homo sapiens (Human) CVCL_4733
M21 cells Skin Homo sapiens (Human) CVCL_D031
SkMEL13 cells Skin Homo sapiens (Human) CVCL_6022
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description miR-31 could suppress tumor growth and enhance sensitivity to dacarbazine (DTIC) by down-regulating SOX10 mainly via inhibiting PI3k/AkT signaling pathway in melanoma.
Doxorubicin
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: hsa-mir-301 [8]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/FAKT signaling pathway Activation hsa04151
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
SkMEL1 cells Skin Homo sapiens (Human) CVCL_0068
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Colony formation assay; Annexin V-fluorescein isothiocyanate (FITC) apoptosis analysis; Wound scratch healing or transwell invasion assay
Mechanism Description PTEN can interact with AkT and FAk and inhibit their activity through their dephosphorylation, Akt and FAk signaling pathways are involved in miR301a/PTEN-promoting malignant phenotypes in MM cells, miR301a promotes MM progression via activation of Akt and FAk signaling pathways by down regulating PTEN.
Key Molecule: hsa-mir-424 [10]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
U251 cells Brain Homo sapiens (Human) CVCL_0021
HEK293T cells Kidney Homo sapiens (Human) CVCL_0063
PARP cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Phosphatase and tensin homolog (PTEN) [8]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/FAKT signaling pathway Activation hsa04151
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
SkMEL1 cells Skin Homo sapiens (Human) CVCL_0068
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Colony formation assay; Annexin V-fluorescein isothiocyanate (FITC) apoptosis analysis; Wound scratch healing or transwell invasion assay
Mechanism Description PTEN can interact with AkT and FAk and inhibit their activity through their dephosphorylation, Akt and FAk signaling pathways are involved in miR301a/PTEN-promoting malignant phenotypes in MM cells, miR301a promotes MM progression via activation of Akt and FAk signaling pathways by down regulating PTEN.
Key Molecule: Programmed cell death protein 4 (PDCD4) [10]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
U251 cells Brain Homo sapiens (Human) CVCL_0021
HEK293T cells Kidney Homo sapiens (Human) CVCL_0063
PARP cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.
Fluorouracil
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: Histone-lysine N-methyltransferase EZH2 (EZH2) [12]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Fluorouracil
 Drug Info 
Molecule Alteration Methylation
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model B16-BL6 cells Skin Homo sapiens (Human) CVCL_0157
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 WST-8 assay
Mechanism Description These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment.
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [12]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Fluorouracil
 Drug Info 
Molecule Alteration Methylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Colon-26 carcinoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 WST-8 assay
Mechanism Description These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment.
Nivolumab
Click to Show/Hide
Drug Resistance 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) [28]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Nivolumab
 Drug 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
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
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) [28]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Nivolumab
 Drug Info 
Molecule Alteration Missense mutation
p.V600K (c.1798_1799delGTinsAA)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Oxaliplatin
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: Histone-lysine N-methyltransferase EZH2 (EZH2) [12]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Oxaliplatin
 Drug Info 
Molecule Alteration Methylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model B16-BL6 cells Skin Homo sapiens (Human) CVCL_0157
Colon-26 carcinoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 WST-8 assay
Mechanism Description These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment.
Palbociclib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Cyclin-dependent kinase 4 (CDK4) [30]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Palbociclib
 Drug Info 
Molecule Alteration Missense mutation
p.R24C (c.70C>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Skin sample N.A.
Experiment for
Molecule Alteration		 Western blot analysis; Immunohistochemistry assay
Experiment for
Drug Resistance		 SRB assay
Pembrolizumab
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [31]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Pembrolizumab
 Drug Info 
Molecule Alteration Missense mutation
p.Q61R
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.24  Å
PDB: 7F68
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.46
TM score: 0.94384
Amino acid change:
Q61R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
S
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
R
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
D
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
-
L
-
N
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Circulating tumour DNA (ctDNA) analysis; Whole genome plasma DNA sequencing assay
Experiment for
Drug Resistance		 Computer tomography (CT) assay; Positron emission tomography assay
Mechanism Description Mutations in NRAS have been found in 8-26% of patients with acquired resistance to BRAF inhibitors. We analysed the presence of NRASQ61k and NRASQ61R in the ctDNA extracted from 7 melanoma patients with progressive disease who had previously responded to treatment with vemurafenib (n = 2) or dabrafenib/trametinib (n = 5). Two samples were positive for NRASQ61k and one sample had an NRASQ61R mutation, all three were derived from patients treated with dabrafenib/trametinib.
Trametinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 1 (MEK1) [17]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V60E (c.179T>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
A2058 cells Skin Homo sapiens (Human) CVCL_1059
WM2664 cells Skin Homo sapiens (Human) CVCL_2765
SkMEL28 cells Skin Homo sapiens (Human) CVCL_0526
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [32]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.L597Q (c.1790T>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [33]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.K601E (c.1801A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Melanoma thyroid metastasis N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.K601E (c.1801A>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [34]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.K601E (c.1801A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [34]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.L597R (c.1790T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Whole-gene resequencing assay
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [34]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600R (c.1798_1799delGTinsAG)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [35]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.L597V (c.1789C>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Skin N.A.
Experiment for
Molecule Alteration		 Tumour genotyping assay
Mechanism Description The missense mutation p.L597V (c.1789C>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [33]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.L597S (c.1789_1790delCTinsTC)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Melanoma thyroid metastasis N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.L597S (c.1789_1790delCTinsTC) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [36]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.D594G (c.1781A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ERK signaling pathway Activation hsa04210
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
H1650 cells Pleural effusion Homo sapiens (Human) CVCL_4V01
HTB-56 cells Pleural effusion Homo sapiens (Human) CVCL_0236
HTB-38 cells Colon Homo sapiens (Human) CVCL_0320
HTB-183 cells Lymph node Homo sapiens (Human) CVCL_1577
H661 cells Lymph node Homo sapiens (Human) CVCL_1577
H508 cells Abdominal wall Homo sapiens (Human) CVCL_1564
H2405 cells Lung Homo sapiens (Human) CVCL_1551
H1666 cells Pleural effusion Homo sapiens (Human) CVCL_1485
H1395 cells Lung Homo sapiens (Human) CVCL_1467
CRL-5944 cells Ascites Homo sapiens (Human) CVCL_1551
CRL-5885 cells Pleural effusion Homo sapiens (Human) CVCL_1485
CRL-5883 cells Pleural effusion Homo sapiens (Human) CVCL_1483
CRL-5868 cells Lung Homo sapiens (Human) CVCL_1467
CRL-5803 cells Lymph node Homo sapiens (Human) CVCL_0060
CCL-253 cells Abdominal wall Homo sapiens (Human) CVCL_1564
CCL-185 cells Bowel Homo sapiens (Human) CVCL_0023
Calu-6 cells Lung Homo sapiens (Human) CVCL_0236
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Researchers defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.L597S (c.1789_1790delCTinsTC)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vitro Model Skin sample N.A.
In Vivo Model Mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Crystal violet staining assay
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [37]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.D594V (c.1781A>T)
 Molecule Info 
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.D594V (c.1781A>T) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [38]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Synonymous
p.K601K (c.1803A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Synonymous
p.L597L (c.1791A>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [34]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.K601R (c.1802A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [35]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.L597R (c.1790T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293H cells Fetal kidney Homo sapiens (Human) CVCL_ZK99
Experiment for
Molecule Alteration		 Whole genome sequencing assay
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [23]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600K (c.1798_1799delGTinsAA)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Trametinib/Dabrafenib
Click to Show/Hide
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) [39]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Trametinib/Dabrafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V600X (c.1798_1799)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Skin N.A.
Experiment for
Drug Resistance		 Tumor evaluation assay
Investigative Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Orthocresol
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Growth arrest specific 5 (GAS5) [3]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Orthocresol
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Skin cutaneous melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 3.29E-02
Fold-change: 1.53E-01
Z-score: 2.14E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
A431 cells Skin Homo sapiens (Human) CVCL_0037
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description 2-O-Methylmagnolol upregulates the long non-coding RNA, GAS5, and enhances apoptosis in skin cancer cells. Overexpression of LncRNA GAS5 inhibited cell proliferation and promoted cell apoptosis in skin cancer cells.
Clinical Trial Drug(s)
6 drug(s) in total
Click to Show/Hide the Full List of Drugs
Capivasertib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [49]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Capivasertib
 Drug Info 
Molecule Alteration Missense mutation
p.H1968Y (c.5902C>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model HEK 292T cells Kidney Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Cobimetinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Cobimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.L597S (c.1789_1790delCTinsTC)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vitro Model Skin sample N.A.
In Vivo Model Mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Crystal violet staining assay
Crenolanib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [50]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.P577S (c.1729C>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The missense mutation p.P577S (c.1729C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [50]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.V658A (c.1973T>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The missense mutation p.V658A (c.1973T>C) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [50]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.R841K (c.2522G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The missense mutation p.R841K (c.2522G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [50]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.H845Y (c.2533C>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The missense mutation p.H845Y (c.2533C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [50]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.G853D (c.2558G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The missense mutation p.G853D (c.2558G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [50]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.P577S (c.1729C>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The missense mutation p.P577S (c.1729C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [50]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.V658A (c.1973T>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The missense mutation p.V658A (c.1973T>C) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [50]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.R841K (c.2522G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The missense mutation p.R841K (c.2522G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [50]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.H845Y (c.2533C>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The missense mutation p.H845Y (c.2533C>T) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [50]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.G853D (c.2558G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The missense mutation p.G853D (c.2558G>A) in gene PDGFRA cause the sensitivity of Crenolanib by aberration of the drug's therapeutic target
Ganetespib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [51]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Ganetespib
 Drug 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
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 WST-1 cell proliferation assay
Refametinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [52]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Refametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600X (c.1798_1799)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Mechanism Description The missense mutation p.V600X (c.1798_1799) in gene BRAF cause the resistance of Refametinib by aberration of the drug's therapeutic target
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [53]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Refametinib
 Drug 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
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
A375 cells Skin Homo sapiens (Human) CVCL_0132
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
A431 cells Skin Homo sapiens (Human) CVCL_0037
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
BxPc3 cells Pancreas Homo sapiens (Human) CVCL_0186
SkMEL28 cells Skin Homo sapiens (Human) CVCL_0526
In Vivo Model Female athymic nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Biochemical kinase assays
Experiment for
Drug Resistance		 CellTiter 96 Aqueous One assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Refametinib by unusual activation of pro-survival pathway
Selumetinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 1 (MEK1) [54]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q56P (c.167A>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
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.Q56P (c.167A>C) in gene MAP2K1 cause the resistance of Selumetinib by aberration of the drug's therapeutic target
Key Molecule: MAPK/ERK kinase 1 (MEK1) [54]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.I103N (c.308T>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
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 Selumetinib by aberration of the drug's therapeutic target
Key Molecule: MAPK/ERK kinase 1 (MEK1) [54]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.L115P (c.344T>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
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 Selumetinib by aberration of the drug's therapeutic target
Key Molecule: MAPK/ERK kinase 1 (MEK1) [54]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.P124S (c.370C>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
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.P124S (c.370C>T) in gene MAP2K1 cause the resistance of Selumetinib by aberration of the drug's therapeutic target
Key Molecule: MAPK/ERK kinase 1 (MEK1) [54]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.P124L (c.371C>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
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 Selumetinib by aberration of the drug's therapeutic target
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [55]
Resistant Disease Melanoma [ICD-11: 2C30.0]
Resistant Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61L (c.182A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
A2058 cells Skin Homo sapiens (Human) CVCL_1059
A375 cells Skin Homo sapiens (Human) CVCL_0132
A375 cells Skin Homo sapiens (Human) CVCL_0132
A375 cells Skin Homo sapiens (Human) CVCL_0132
WM2664 cells Skin Homo sapiens (Human) CVCL_2765
SkMEL 30 cells Skin Homo sapiens (Human) CVCL_0039
SkMEL 2 cells Skin Homo sapiens (Human) CVCL_0069
SH4 cells Skin Mus musculus (Mouse) CVCL_7702
MEXF-535 cells Skin Homo sapiens (Human) N.A.
MEXF-1792 cells Skin Homo sapiens (Human) N.A.
MEXF-1341 cells Skin Homo sapiens (Human) N.A.
M14 cells Hypodermis Homo sapiens (Human) CVCL_1395
GAK cells Lnguinal lymph node Homo sapiens (Human) CVCL_1225
Colo829 cells Skin Homo sapiens (Human) CVCL_1137
In Vivo Model Female NIH nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Crystallization assay; X-ray data collection and structure determination assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; Enzymatic kinase assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [55]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61K (c.181C>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
|
-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
-
F
-
Q
0
|
S
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
A2058 cells Skin Homo sapiens (Human) CVCL_1059
A375 cells Skin Homo sapiens (Human) CVCL_0132
A375 cells Skin Homo sapiens (Human) CVCL_0132
A375 cells Skin Homo sapiens (Human) CVCL_0132
WM2664 cells Skin Homo sapiens (Human) CVCL_2765
SkMEL 30 cells Skin Homo sapiens (Human) CVCL_0039
SkMEL 2 cells Skin Homo sapiens (Human) CVCL_0069
SH4 cells Skin Mus musculus (Mouse) CVCL_7702
MEXF-535 cells Skin Homo sapiens (Human) N.A.
MEXF-1792 cells Skin Homo sapiens (Human) N.A.
MEXF-1341 cells Skin Homo sapiens (Human) N.A.
M14 cells Hypodermis Homo sapiens (Human) CVCL_1395
GAK cells Lnguinal lymph node Homo sapiens (Human) CVCL_1225
Colo829 cells Skin Homo sapiens (Human) CVCL_1137
In Vivo Model Female NIH nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Crystallization assay; X-ray data collection and structure determination assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; Enzymatic kinase assay
Key Molecule: GTPase Nras (NRAS) [56]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61K (c.181C>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
|
-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
-
F
-
Q
0
|
S
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
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V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
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170
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K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Skin N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Selumetinib by aberration of the drug's therapeutic target
Key Molecule: GTPase Nras (NRAS) [57]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
Sensitive Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61R (c.182A>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.24  Å
PDB: 7F68
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.46
TM score: 0.94384
Amino acid change:
Q61R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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0
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S
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M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
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G
G
A
A
G
G
G
G
V
V
G
G
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A
A
L
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20
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H
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30
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D
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D
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40
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V
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G
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E
50
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T
T
C
C
L
L
L
L
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L
D
D
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A
60
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G
G
Q
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E
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E
Y
Y
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S
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A
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M
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R
D
D
70
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Q
Q
Y
Y
M
M
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R
T
T
G
G
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E
G
G
F
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80
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C
C
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F
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N
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90
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100
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110
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120
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130
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A
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G
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140
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P
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R
150
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Q
Q
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G
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160
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Y
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R
M
M
K
K
170
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K
-
L
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N
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Drug Resistance		 MTD assay
Mechanism Description The missense mutation p.Q61R (c.182A>G) in gene NRAS cause the sensitivity of Selumetinib by unusual activation of pro-survival pathway
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Ref 4 Methylation-Mediated Silencing of MicroRNA-211 Decreases the Sensitivity of Melanoma Cells to Cisplatin. Med Sci Monit. 2019 Mar 1;25:1590-1599. doi: 10.12659/MSM.911862.
Ref 5 miR-326-histone deacetylase-3 feedback loop regulates the invasion and tumorigenic and angiogenic response to anti-cancer drugs. J Biol Chem. 2014 Oct 3;289(40):28019-39. doi: 10.1074/jbc.M114.578229. Epub 2014 Aug 19.
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Ref 7 miR-216b enhances the efficacy of vemurafenib by targeting Beclin-1, UVRAG and ATG5 in melanoma. Cell Signal. 2018 Jan;42:30-43. doi: 10.1016/j.cellsig.2017.09.024. Epub 2017 Oct 2.
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