Drug Information

Drug (ID: DG00306) and It's Reported Resistant Information
Name
Vemurafenib
Synonyms
PLX4032; RG7204; RO5185426; Zelboraf (TN); Vemurafenib (BRAF inhibitor)
    Click to Show/Hide
Indication
In total 1 Indication(s)
Melanoma [ICD-11: 2C30]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
Melanoma [ICD-11: 2C30]
[2], [3]
Multiple myeloma [ICD-11: 2A83]
[4]
Thyroid cancer [ICD-11: 2D10]
[5]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Melanoma [ICD-11: 2C30]
[1]
Target Serine/threonine-protein kinase B-raf (BRAF) BRAF_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C23H18ClF2N3O3S
IsoSMILES
CCCS(=O)(=O)NC1=C(C(=C(C=C1)F)C(=O)C2=CNC3=C2C=C(C=N3)C4=CC=C(C=C4)Cl)F
InChI
1S/C23H18ClF2N3O3S/c1-2-9-33(31,32)29-19-8-7-18(25)20(21(19)26)22(30)17-12-28-23-16(17)10-14(11-27-23)13-3-5-15(24)6-4-13/h3-8,10-12,29H,2,9H2,1H3,(H,27,28)
InChIKey
GPXBXXGIAQBQNI-UHFFFAOYSA-N
PubChem CID
42611257
ChEBI ID
CHEBI:63637
TTD Drug ID
D0Y9EW
VARIDT ID
DR00711
INTEDE ID
DR1677
DrugBank ID
DB08881
Type(s) of Resistant Mechanism of This Drug due to Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Multiple myeloma [ICD-11: 2A83]
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) [4]
Resistant Disease Multiple myeloma [ICD-11: 2A83.0]
 Disease 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
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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
C
G
G
G
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V
G
G
K
K
S
S
A
A
L
L
20
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T
T
I
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Q
Q
L
L
I
I
Q
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N
N
H
H
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30
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D
D
E
E
Y
Y
D
D
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P
T
T
I
I
E
E
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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
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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
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
|
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
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H
H
H
Y
Y
R
R
E
E
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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
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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
|
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
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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
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Ion Torrent semiconductor-based targeted resequencing assay
Experiment for
Drug Resistance		 Whole-body magnetic resonance imaging (MRI) assay
Mechanism Description Although all 5 reference lesions biopsied in month 10 still harbored a BRAFV600E mutation in all MM cells, an additio.l monoallelic NRAS mutation was detectable in each of the 3 lesions resistant to the full dose of vemurafenib. Of note, each lesion harbored a unique, independent, yet clo.l NRAS mutation (NRAS G13R, NRAS G12A, and NRAS Q61H, respectively).
Key Molecule: GTPase Nras (NRAS) [4]
Resistant Disease Multiple myeloma [ICD-11: 2A83.0]
 Disease Info 
Molecule Alteration Missense mutation
p.G12A
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.45  Å
PDB: 8TBJ
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.06
TM score: 0.96454
Amino acid change:
G12A
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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0
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G
S
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
A
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
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T
T
I
I
Q
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
I
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
|
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
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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
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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
|
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
|
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		 Ion Torrent semiconductor-based targeted resequencing assay
Experiment for
Drug Resistance		 Whole-body magnetic resonance imaging (MRI) assay
Mechanism Description Although all 5 reference lesions biopsied in month 10 still harbored a BRAFV600E mutation in all MM cells, an additio.l monoallelic NRAS mutation was detectable in each of the 3 lesions resistant to the full dose of vemurafenib. Of note, each lesion harbored a unique, independent, yet clo.l NRAS mutation (NRAS G13R, NRAS G12A, and NRAS Q61H, respectively).
Melanoma [ICD-11: 2C30]
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) [6], [7], [8]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease 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
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V
V
V
V
V
10
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G
A
A
G
G
G
G
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G
G
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K
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S
A
A
L
L
20
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T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
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D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
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40
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Y
Y
R
R
K
K
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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
K
E
E
E
E
Y
Y
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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
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
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D
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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
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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
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
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) [2], [3]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease 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
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T
T
I
I
Q
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
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
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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
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
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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
|
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
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) [9]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease 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
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G
-
R
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E
-
N
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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) [9]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease 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) [6], [7], [8]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease 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) [8]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease 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) [7]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease 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) [8]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease 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) [8]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease 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) [8]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease 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) [8]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease 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.
Thyroid cancer [ICD-11: 2D10]
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) [5]
Resistant Disease Papillary thyroid carcinoma [ICD-11: 2D10.1]
 Disease Info 
Molecule Alteration Missense mutation
p.V600E
 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 Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Low throughput experiment assay
Mechanism Description BRAFV600E is the most common mutation in PTC, occurring in about 60% of PTC tumors, and has been described as a clonal event since it occurs in the majority of tumor cells. BRAFV600E PTC exhibits primary resistance to RAI treatment, higher rates of tumor recurrence and metastases, and lower survival rates. Remarkably, the BRAFV600E mutation not only promotes thyroid tumor cell proliferation, adhesion, migration and invasion, but also up-regulates epigenetic pathways that silence expression of the sodium/iodide symporter. This blocks iodide uptake, which may be one cause of primary resistance to RAI. Present in other cancers, including 40-70% of malignant melanomas and 10% of colorectal cancers, BRAFV600E positive tumors provide one important case study for the evolution of drug resistance.
References
Ref 1 miR-204-5p and miR-211-5p Contribute to BRAF Inhibitor Resistance in Melanoma. Cancer Res. 2018 Feb 15;78(4):1017-1030. doi: 10.1158/0008-5472.CAN-17-1318. Epub 2017 Dec 11.
Ref 2 COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010 Dec 16;468(7326):968-72. doi: 10.1038/nature09627. Epub 2010 Nov 24.
Ref 3 Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013 Aug;10(8):472-84. doi: 10.1038/nrclinonc.2013.110. Epub 2013 Jul 9.
Ref 4 Spatially divergent clonal evolution in multiple myeloma: overcoming resistance to BRAF inhibition. Blood. 2016 Apr 28;127(17):2155-7. doi: 10.1182/blood-2015-12-686782. Epub 2016 Feb 16.
Ref 5 Evolution of resistance to thyroid cancer therapy. Aging (Albany NY). 2016 Aug;8(8):1576-7. doi: 10.18632/aging.101030.
Ref 6 Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010 Dec 16;468(7326):973-7. doi: 10.1038/nature09626. Epub 2010 Nov 24.
Ref 7 The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014 Jan;4(1):94-109. doi: 10.1158/2159-8290.CD-13-0617. Epub 2013 Nov 21.
Ref 8 Tumor heterogeneity and plasticity as elusive drivers for resistance to MAPK pathway inhibition in melanoma. Oncogene. 2015 Jun 4;34(23):2951-7. doi: 10.1038/onc.2014.249. Epub 2014 Aug 11.
Ref 9 The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma .Expert Opin Drug Discov. 2016 Sep;11(9):907-16. doi: 10.1080/17460441.2016.1201057. Epub 2016 Jun 23. 10.1080/17460441.2016.1201057

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