Disease Information

General Information of the Disease (ID: DIS00101)
Name
Thyroid cancer
ICD
ICD-11: 2D10
Resistance Map
Type(s) of Resistant Mechanism of This Disease with Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
7 drug(s) in total
Click to Show/Hide the Full List of Drugs
Cabozantinib
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
L
T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
TPC-1 cells Thyroid Homo sapiens (Human) CVCL_6298
MZ-CRC-1 cells Pleural effusion Homo sapiens (Human) CVCL_A656
MTC-TT cells Thyroid gland Homo sapiens (Human) CVCL_1774
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.M918T (c.2753T>C) in gene RET cause the sensitivity of Cabozantinib by aberration of the drug's therapeutic target
Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [2]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
L
T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Dabrafenib/Trametinib
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) [3]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
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
Pralsetinib
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [4]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug Pralsetinib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
L
T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model TPC-1 cells Thyroid Homo sapiens (Human) CVCL_6298
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
TT cells Thyroid gland Homo sapiens (Human) CVCL_1774
MZ-CRC-1 cells Pleural effusion Homo sapiens (Human) CVCL_A656
LC2/ad cells Pleural effusion Homo sapiens (Human) CVCL_1373
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Selpercatinib
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [5]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug Selpercatinib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
L
T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
In Vivo Model Mouse PDX model Mus musculus
Mechanism Description LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations.
Trametinib/Dabrafenib
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) [6]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug Trametinib/Dabrafenib
 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
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
Vandetanib
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [7]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug Vandetanib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
L
T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 PCR
Vemurafenib
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) [8]
Resistant Disease Papillary thyroid carcinoma [ICD-11: 2D10.1]
Resistant Drug Vemurafenib
 Drug 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.
Clinical Trial Drug(s)
4 drug(s) in total
Click to Show/Hide the Full List of Drugs
Selumetinib
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) [9]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug Selumetinib
 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
Cell Pathway Regulation BRAF/MEK/MAPK signaling pathway Inhibition hsa04010
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
BCPAP cells Thyroid Homo sapiens (Human) CVCL_0153
SW1736 cells Thyroid Homo sapiens (Human) CVCL_3883
C643 cells Thyroid gland Homo sapiens (Human) CVCL_5969
CAL62 cells Thyroid gland Homo sapiens (Human) CVCL_1112
In Vivo Model Athymic nude mouse PDX xenografts model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay; Immunoprecipitation assy
Experiment for
Drug Resistance		 SRB staining assay; Promega assay
Mechanism Description Activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib.
AZD1480
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [10]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug AZD1480
 Drug Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
L
T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model TPC-1 cells Thyroid Homo sapiens (Human) CVCL_6298
C643 cells Thyroid gland Homo sapiens (Human) CVCL_5969
K1 cells Thyroid Homo sapiens (Human) CVCL_2537
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 TUNEL assay
Mechanism Description The missense mutation p.M918T (c.2753T>C) in gene RET cause the sensitivity of AZD1480 by unusual activation of pro-survival pathway
RO-5126766 free base
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) [11]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug RO-5126766 free base
 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
Cell Pathway Regulation ERK signaling pathway Inhibition hsa04210
Perifosine
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: PI3-kinase alpha (PIK3CA) [12]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug Perifosine
 Drug Info 
Molecule Alteration Missense mutation
p.H1047R (c.3140A>G)
 Molecule Info 
Wild Type Structure Method: Electron microscopy Resolution: 2.41  Å
PDB: 8DCP
Mutant Type Structure Method: X-ray diffraction Resolution: 2.61  Å
PDB: 8V8V
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.09
TM score: 0.95656
Amino acid change:
H1047R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
-
S
-
Y
-
Y
-
H
-
H
-
H
-
-20
|
H
-
H
-
H
-
D
-
Y
-
D
-
I
-
P
-
T
-
T
-
-10
|
E
-
N
-
L
-
Y
-
F
-
Q
-
G
G
A
A
M
M
G
G
0
|
S
S
M
M
P
P
P
P
R
R
P
P
S
S
S
S
G
G
E
E
10
|
L
L
W
W
G
G
I
I
H
H
L
L
M
M
P
P
P
P
R
R
20
|
I
I
L
L
V
V
E
E
C
C
L
L
L
L
P
P
N
N
G
G
30
|
M
M
I
I
V
V
T
T
L
L
E
E
C
C
L
L
R
R
E
E
40
|
A
A
T
T
L
L
I
I
T
T
I
I
K
K
H
H
E
E
L
L
50
|
F
F
K
K
E
E
A
A
R
R
K
K
Y
Y
P
P
L
L
H
H
60
|
Q
Q
L
L
L
L
Q
Q
D
D
E
E
S
S
S
S
Y
Y
I
I
70
|
F
F
V
V
S
S
V
V
T
T
Q
Q
E
E
A
A
E
E
R
R
80
|
E
E
E
E
F
F
F
F
D
D
E
E
T
T
R
R
R
R
L
L
90
|
C
C
D
D
L
L
R
R
L
L
F
F
Q
Q
P
P
F
F
L
L
100
|
K
K
V
V
I
I
E
E
P
P
V
V
G
G
N
N
R
R
E
E
110
|
E
E
K
K
I
I
L
L
N
N
R
R
E
E
I
I
G
G
F
F
120
|
A
A
I
I
G
G
M
M
P
P
V
V
C
C
E
E
F
F
D
D
130
|
M
M
V
V
K
K
D
D
P
P
E
E
V
V
Q
Q
D
D
F
F
140
|
R
R
R
R
N
N
I
I
L
L
N
N
V
V
C
C
K
K
E
E
150
|
A
A
V
V
D
D
L
L
R
R
D
D
L
L
N
N
S
S
P
P
160
|
H
H
S
S
R
R
A
A
M
M
Y
Y
V
V
Y
Y
P
P
P
P
170
|
N
N
V
V
E
E
S
S
S
S
P
P
E
E
L
L
P
P
K
K
180
|
H
H
I
I
Y
Y
N
N
K
K
L
L
D
D
K
K
G
G
Q
Q
190
|
I
I
I
I
V
V
V
V
I
I
W
W
V
V
I
I
V
V
S
S
200
|
P
P
N
N
N
N
D
D
K
K
Q
Q
K
K
Y
Y
T
T
L
L
210
|
K
K
I
I
N
N
H
H
D
D
C
C
V
V
P
P
E
E
Q
Q
220
|
V
V
I
I
A
A
E
E
A
A
I
I
R
R
K
K
K
K
T
T
230
|
R
R
S
S
M
M
L
L
L
L
S
S
S
S
E
E
Q
Q
L
L
240
|
K
K
L
L
C
C
V
V
L
L
E
E
Y
Y
Q
Q
G
G
K
K
250
|
Y
Y
I
I
L
L
K
K
V
V
C
C
G
G
C
C
D
D
E
E
260
|
Y
Y
F
F
L
L
E
E
K
K
Y
Y
P
P
L
L
S
S
Q
Q
270
|
Y
Y
K
K
Y
Y
I
I
R
R
S
S
C
C
I
I
M
M
L
L
280
|
G
G
R
R
M
M
P
P
N
N
L
L
M
M
L
L
M
M
A
A
290
|
K
K
E
E
S
S
L
L
Y
Y
S
S
Q
Q
L
L
P
P
M
M
300
|
D
D
C
C
F
F
T
T
M
M
P
P
S
S
Y
Y
S
S
R
R
310
|
R
R
I
I
S
S
T
T
A
A
T
T
P
P
Y
Y
M
M
N
N
320
|
G
G
E
E
T
T
S
S
T
T
K
K
S
S
L
L
W
W
V
V
330
|
I
I
N
N
S
S
A
A
L
L
R
R
I
I
K
K
I
I
L
L
340
|
C
C
A
A
T
T
Y
Y
V
V
N
N
V
V
N
N
I
I
R
R
350
|
D
D
I
I
D
D
K
K
I
I
Y
Y
V
V
R
R
T
T
G
G
360
|
I
I
Y
Y
H
H
G
G
G
G
E
E
P
P
L
L
C
C
D
D
370
|
N
N
V
V
N
N
T
T
Q
Q
R
R
V
V
P
P
C
C
S
S
380
|
N
N
P
P
R
R
W
W
N
N
E
E
W
W
L
L
N
N
Y
Y
390
|
D
D
I
I
Y
Y
I
I
P
P
D
D
L
L
P
P
R
R
A
A
400
|
A
A
R
R
L
L
C
C
L
L
S
S
I
I
C
C
S
S
V
V
410
|
K
K
G
G
R
R
K
K
G
G
A
A
K
K
E
E
E
E
H
H
420
|
C
C
P
P
L
L
A
A
W
W
G
G
N
N
I
I
N
N
L
L
430
|
F
F
D
D
Y
Y
T
T
D
D
T
T
L
L
V
V
S
S
G
G
440
|
K
K
M
M
A
A
L
L
N
N
L
L
W
W
P
P
V
V
P
P
450
|
H
H
G
G
L
L
E
E
D
D
L
L
L
L
N
N
P
P
I
I
460
|
G
G
V
V
T
T
G
G
S
S
N
N
P
P
N
N
K
K
E
E
470
|
T
T
P
P
C
C
L
L
E
E
L
L
E
E
F
F
D
D
W
W
480
|
F
F
S
S
S
S
V
V
V
V
K
K
F
F
P
P
D
D
M
M
490
|
S
S
V
V
I
I
E
E
E
E
H
H
A
A
N
N
W
W
S
S
500
|
V
V
S
S
R
R
E
E
A
A
G
G
F
F
S
S
Y
Y
S
S
510
|
H
H
A
A
G
G
L
L
S
S
N
N
R
R
L
L
A
A
R
R
520
|
D
D
N
N
E
E
L
L
R
R
E
E
N
N
D
D
K
K
E
E
530
|
Q
Q
L
L
K
K
A
A
I
I
S
S
T
T
R
R
D
D
P
P
540
|
L
L
S
S
E
E
I
I
T
T
E
E
Q
Q
E
E
K
K
D
D
550
|
F
F
L
L
W
W
S
S
H
H
R
R
H
H
Y
Y
C
C
V
V
560
|
T
T
I
I
P
P
E
E
I
I
L
L
P
P
K
K
L
L
L
L
570
|
L
L
S
S
V
V
K
K
W
W
N
N
S
S
R
R
D
D
E
E
580
|
V
V
A
A
Q
Q
M
M
Y
Y
C
C
L
L
V
V
K
K
D
D
590
|
W
W
P
P
P
P
I
I
K
K
P
P
E
E
Q
Q
A
A
M
M
600
|
E
E
L
L
L
L
D
D
C
C
N
N
Y
Y
P
P
D
D
P
P
610
|
M
M
V
V
R
R
G
G
F
F
A
A
V
V
R
R
C
C
L
L
620
|
E
E
K
K
Y
Y
L
L
T
T
D
D
D
D
K
K
L
L
S
S
630
|
Q
Q
Y
Y
L
L
I
I
Q
Q
L
L
V
V
Q
Q
V
V
L
L
640
|
K
K
Y
Y
E
E
Q
Q
Y
Y
L
L
D
D
N
N
L
L
L
L
650
|
V
V
R
R
F
F
L
L
L
L
K
K
K
K
A
A
L
L
T
T
660
|
N
N
Q
Q
R
R
I
I
G
G
H
H
F
F
F
F
F
F
W
W
670
|
H
H
L
L
K
K
S
S
E
E
M
M
H
H
N
N
K
K
T
T
680
|
V
V
S
S
Q
Q
R
R
F
F
G
G
L
L
L
L
L
L
E
E
690
|
S
S
Y
Y
C
C
R
R
A
A
C
C
G
G
M
M
Y
Y
L
L
700
|
K
K
H
H
L
L
N
N
R
R
Q
Q
V
V
E
E
A
A
M
M
710
|
E
E
K
K
L
L
I
I
N
N
L
L
T
T
D
D
I
I
L
L
720
|
K
K
Q
Q
E
E
K
K
K
K
D
D
E
E
T
T
Q
Q
K
K
730
|
V
V
Q
Q
M
M
K
K
F
F
L
L
V
V
E
E
Q
Q
M
M
740
|
R
R
R
R
P
P
D
D
F
F
M
M
D
D
A
A
L
L
Q
Q
750
|
G
G
F
F
L
L
S
S
P
P
L
L
N
N
P
P
A
A
H
H
760
|
Q
Q
L
L
G
G
N
N
L
L
R
R
L
L
E
E
E
E
C
C
770
|
R
R
I
I
M
M
S
S
S
S
A
A
K
K
R
R
P
P
L
L
780
|
W
W
L
L
N
N
W
W
E
E
N
N
P
P
D
D
I
I
M
M
790
|
S
S
E
E
L
L
L
L
F
F
Q
Q
N
N
N
N
E
E
I
I
800
|
I
I
F
F
K
K
N
N
G
G
D
D
D
D
L
L
R
R
Q
Q
810
|
D
D
M
M
L
L
T
T
L
L
Q
Q
I
I
I
I
R
R
I
I
820
|
M
M
E
E
N
N
I
I
W
W
Q
Q
N
N
Q
Q
G
G
L
L
830
|
D
D
L
L
R
R
M
M
L
L
P
P
Y
Y
G
G
C
C
L
L
840
|
S
S
I
I
G
G
D
D
C
C
V
V
G
G
L
L
I
I
E
E
850
|
V
V
V
V
R
R
N
N
S
S
H
H
T
T
I
I
M
M
Q
Q
860
|
I
I
Q
Q
C
C
K
K
G
G
G
G
L
L
K
K
G
G
A
A
870
|
L
L
Q
Q
F
F
N
N
S
S
H
H
T
T
L
L
H
H
Q
Q
880
|
W
W
L
L
K
K
D
D
K
K
N
N
K
K
G
G
E
E
I
I
890
|
Y
Y
D
D
A
A
A
A
I
I
D
D
L
L
F
F
T
T
R
R
900
|
S
S
C
C
A
A
G
G
Y
Y
C
C
V
V
A
A
T
T
F
F
910
|
I
I
L
L
G
G
I
I
G
G
D
D
R
R
H
H
N
N
S
S
920
|
N
N
I
I
M
M
V
V
K
K
D
D
D
D
G
G
Q
Q
L
L
930
|
F
F
H
H
I
I
D
D
F
F
G
G
H
H
F
F
L
L
D
D
940
|
H
H
K
K
K
K
K
K
K
K
F
F
G
G
Y
Y
K
K
R
R
950
|
E
E
R
R
V
V
P
P
F
F
V
V
L
L
T
T
Q
Q
D
D
960
|
F
F
L
L
I
I
V
V
I
I
S
S
K
K
G
G
A
A
Q
Q
970
|
E
E
C
C
T
T
K
K
T
T
R
R
E
E
F
F
E
E
R
R
980
|
F
F
Q
Q
E
E
M
M
C
C
Y
Y
K
K
A
A
Y
Y
L
L
990
|
A
A
I
I
R
R
Q
Q
H
H
A
A
N
N
L
L
F
F
I
I
1000
|
N
N
L
L
F
F
S
S
M
M
M
M
L
L
G
G
S
S
G
G
1010
|
M
M
P
P
E
E
L
L
Q
Q
S
S
F
F
D
D
D
D
I
I
1020
|
A
A
Y
Y
I
I
R
R
K
K
T
T
L
L
A
A
L
L
D
D
1030
|
K
K
T
T
E
E
Q
Q
E
E
A
A
L
L
E
E
Y
Y
F
F
1040
|
M
M
K
K
Q
Q
M
M
N
N
D
D
A
A
H
R
H
H
G
G
1050
|
G
G
W
W
T
T
T
T
K
K
M
M
D
D
W
W
I
I
F
F
1060
|
H
H
T
T
I
I
K
K
Q
Q
H
H
A
A
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model SW1736 cells Thyroid Homo sapiens (Human) CVCL_3883
C643 cells Thyroid gland Homo sapiens (Human) CVCL_5969
HTH7 cells Thyroid gland Homo sapiens (Human) CVCL_6289
SW1736 cells Thyroid Homo sapiens (Human) CVCL_3883
HTH7 cells Thyroid gland Homo sapiens (Human) CVCL_6289
Hth74 cells Thyroid gland Homo sapiens (Human) CVCL_6288
Hth74 cells Thyroid gland Homo sapiens (Human) CVCL_6288
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of Perifosine by unusual activation of pro-survival pathway
Discontinued Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Motesanib
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [13]
Resistant Disease Thyroid gland cancer [ICD-11: 2D10.0]
Resistant Drug Motesanib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
L
T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Medullary thyroid cancer tissue Pleural effusion Homo sapiens (Human) CVCL_A656
Mechanism Description The missense mutation p.M918T (c.2753T>C) in gene RET cause the resistance of Motesanib by unusual activation of pro-survival pathway
Preclinical Drug(s)
9 drug(s) in total
Click to Show/Hide the Full List of Drugs
ALW-II-41-27
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [14]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug ALW-II-41-27
 Drug Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
L
T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model TT cells Thyroid gland Homo sapiens (Human) CVCL_1774
RET/V804M cells Bone marrow Mus musculus (Mouse) CVCL_XZ26
RET/V804L cells N.A. Mus musculus (Mouse) CVCL_XZ25
RET/S891A cells N.A. Homo sapiens (Human) N.A.
RET/M918T cells N.A. Homo sapiens (Human) N.A.
RET/M918T cells N.A. Homo sapiens (Human) N.A.
RET/L790F cells N.A. Homo sapiens (Human) N.A.
RET/E768D cells N.A. Homo sapiens (Human) N.A.
RET/C634R cells N.A. Homo sapiens (Human) N.A.
RET/C634R cells N.A. Homo sapiens (Human) N.A.
RET/A883F cells N.A. Homo sapiens (Human) N.A.
MZ-CRC-1 cells Pleural effusion Homo sapiens (Human) CVCL_A656
RET/V804M cells Bone marrow Mus musculus (Mouse) CVCL_XZ26
RET/E768D cells N.A. Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cell counting assay
CLM3
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) [15]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug CLM3
 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 8305C cells Thyroid Homo sapiens (Human) CVCL_1053
In Vivo Model Male CD nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Human cyclin D1 ELISA assay
Experiment for
Drug Resistance		 WST-1 assay; Cell counting assay; Hoechst uptake assay; Annexin V binding assay
Dasatinib/SCH772984
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) [9]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug Dasatinib/SCH772984
 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
Cell Pathway Regulation BRAF/MEK/MAPK signaling pathway Inhibition hsa04010
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
BCPAP cells Thyroid Homo sapiens (Human) CVCL_0153
SW1736 cells Thyroid Homo sapiens (Human) CVCL_3883
C643 cells Thyroid gland Homo sapiens (Human) CVCL_5969
CAL62 cells Thyroid gland Homo sapiens (Human) CVCL_1112
In Vivo Model Athymic nude mouse PDX xenografts model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay; Immunoprecipitation assy
Experiment for
Drug Resistance		 SRB staining assay; Promega assay
Mechanism Description Activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib.
Dasatinib/Trametinib
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) [9]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug Dasatinib/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 Revealed Based on the Cell Line Data
Cell Pathway Regulation BRAF/MEK/MAPK signaling pathway Inhibition hsa04010
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
BCPAP cells Thyroid Homo sapiens (Human) CVCL_0153
SW1736 cells Thyroid Homo sapiens (Human) CVCL_3883
C643 cells Thyroid gland Homo sapiens (Human) CVCL_5969
CAL62 cells Thyroid gland Homo sapiens (Human) CVCL_1112
In Vivo Model Athymic nude mouse PDX xenografts model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay; Immunoprecipitation assy
Experiment for
Drug Resistance		 SRB staining assay; Promega assay
Mechanism Description Activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib.
HG-6-63-01
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [14]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug HG-6-63-01
 Drug Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
L
T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model TT cells Thyroid gland Homo sapiens (Human) CVCL_1774
RET/V804M cells Bone marrow Mus musculus (Mouse) CVCL_XZ26
RET/V804L cells N.A. Mus musculus (Mouse) CVCL_XZ25
RET/S891A cells N.A. Homo sapiens (Human) N.A.
RET/M918T cells N.A. Homo sapiens (Human) N.A.
RET/M918T cells N.A. Homo sapiens (Human) N.A.
RET/L790F cells N.A. Homo sapiens (Human) N.A.
RET/E768D cells N.A. Homo sapiens (Human) N.A.
RET/C634R cells N.A. Homo sapiens (Human) N.A.
RET/C634R cells N.A. Homo sapiens (Human) N.A.
RET/A883F cells N.A. Homo sapiens (Human) N.A.
MZ-CRC-1 cells Pleural effusion Homo sapiens (Human) CVCL_A656
RET/V804M cells Bone marrow Mus musculus (Mouse) CVCL_XZ26
RET/E768D cells N.A. Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cell counting assay
MK2206
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) [16]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug MK2206
 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 Revealed Based on the Cell Line Data
In Vitro Model SW1736 cells Thyroid Homo sapiens (Human) CVCL_3883
C643 cells Thyroid gland Homo sapiens (Human) CVCL_5969
HTH7 cells Thyroid gland Homo sapiens (Human) CVCL_6289
Hth74 cells Thyroid gland Homo sapiens (Human) CVCL_6288
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.Q61R (c.182A>G) in gene NRAS cause the sensitivity of MK2206 by unusual activation of pro-survival pathway
MK2206/Temsirolimus
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: PI3-kinase alpha (PIK3CA) [16]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug MK2206/Temsirolimus
 Drug Info 
Molecule Alteration Missense mutation
p.H1047R (c.3140A>G)
 Molecule Info 
Wild Type Structure Method: Electron microscopy Resolution: 2.41  Å
PDB: 8DCP
Mutant Type Structure Method: X-ray diffraction Resolution: 2.61  Å
PDB: 8V8V
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.09
TM score: 0.95656
Amino acid change:
H1047R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
-
S
-
Y
-
Y
-
H
-
H
-
H
-
-20
|
H
-
H
-
H
-
D
-
Y
-
D
-
I
-
P
-
T
-
T
-
-10
|
E
-
N
-
L
-
Y
-
F
-
Q
-
G
G
A
A
M
M
G
G
0
|
S
S
M
M
P
P
P
P
R
R
P
P
S
S
S
S
G
G
E
E
10
|
L
L
W
W
G
G
I
I
H
H
L
L
M
M
P
P
P
P
R
R
20
|
I
I
L
L
V
V
E
E
C
C
L
L
L
L
P
P
N
N
G
G
30
|
M
M
I
I
V
V
T
T
L
L
E
E
C
C
L
L
R
R
E
E
40
|
A
A
T
T
L
L
I
I
T
T
I
I
K
K
H
H
E
E
L
L
50
|
F
F
K
K
E
E
A
A
R
R
K
K
Y
Y
P
P
L
L
H
H
60
|
Q
Q
L
L
L
L
Q
Q
D
D
E
E
S
S
S
S
Y
Y
I
I
70
|
F
F
V
V
S
S
V
V
T
T
Q
Q
E
E
A
A
E
E
R
R
80
|
E
E
E
E
F
F
F
F
D
D
E
E
T
T
R
R
R
R
L
L
90
|
C
C
D
D
L
L
R
R
L
L
F
F
Q
Q
P
P
F
F
L
L
100
|
K
K
V
V
I
I
E
E
P
P
V
V
G
G
N
N
R
R
E
E
110
|
E
E
K
K
I
I
L
L
N
N
R
R
E
E
I
I
G
G
F
F
120
|
A
A
I
I
G
G
M
M
P
P
V
V
C
C
E
E
F
F
D
D
130
|
M
M
V
V
K
K
D
D
P
P
E
E
V
V
Q
Q
D
D
F
F
140
|
R
R
R
R
N
N
I
I
L
L
N
N
V
V
C
C
K
K
E
E
150
|
A
A
V
V
D
D
L
L
R
R
D
D
L
L
N
N
S
S
P
P
160
|
H
H
S
S
R
R
A
A
M
M
Y
Y
V
V
Y
Y
P
P
P
P
170
|
N
N
V
V
E
E
S
S
S
S
P
P
E
E
L
L
P
P
K
K
180
|
H
H
I
I
Y
Y
N
N
K
K
L
L
D
D
K
K
G
G
Q
Q
190
|
I
I
I
I
V
V
V
V
I
I
W
W
V
V
I
I
V
V
S
S
200
|
P
P
N
N
N
N
D
D
K
K
Q
Q
K
K
Y
Y
T
T
L
L
210
|
K
K
I
I
N
N
H
H
D
D
C
C
V
V
P
P
E
E
Q
Q
220
|
V
V
I
I
A
A
E
E
A
A
I
I
R
R
K
K
K
K
T
T
230
|
R
R
S
S
M
M
L
L
L
L
S
S
S
S
E
E
Q
Q
L
L
240
|
K
K
L
L
C
C
V
V
L
L
E
E
Y
Y
Q
Q
G
G
K
K
250
|
Y
Y
I
I
L
L
K
K
V
V
C
C
G
G
C
C
D
D
E
E
260
|
Y
Y
F
F
L
L
E
E
K
K
Y
Y
P
P
L
L
S
S
Q
Q
270
|
Y
Y
K
K
Y
Y
I
I
R
R
S
S
C
C
I
I
M
M
L
L
280
|
G
G
R
R
M
M
P
P
N
N
L
L
M
M
L
L
M
M
A
A
290
|
K
K
E
E
S
S
L
L
Y
Y
S
S
Q
Q
L
L
P
P
M
M
300
|
D
D
C
C
F
F
T
T
M
M
P
P
S
S
Y
Y
S
S
R
R
310
|
R
R
I
I
S
S
T
T
A
A
T
T
P
P
Y
Y
M
M
N
N
320
|
G
G
E
E
T
T
S
S
T
T
K
K
S
S
L
L
W
W
V
V
330
|
I
I
N
N
S
S
A
A
L
L
R
R
I
I
K
K
I
I
L
L
340
|
C
C
A
A
T
T
Y
Y
V
V
N
N
V
V
N
N
I
I
R
R
350
|
D
D
I
I
D
D
K
K
I
I
Y
Y
V
V
R
R
T
T
G
G
360
|
I
I
Y
Y
H
H
G
G
G
G
E
E
P
P
L
L
C
C
D
D
370
|
N
N
V
V
N
N
T
T
Q
Q
R
R
V
V
P
P
C
C
S
S
380
|
N
N
P
P
R
R
W
W
N
N
E
E
W
W
L
L
N
N
Y
Y
390
|
D
D
I
I
Y
Y
I
I
P
P
D
D
L
L
P
P
R
R
A
A
400
|
A
A
R
R
L
L
C
C
L
L
S
S
I
I
C
C
S
S
V
V
410
|
K
K
G
G
R
R
K
K
G
G
A
A
K
K
E
E
E
E
H
H
420
|
C
C
P
P
L
L
A
A
W
W
G
G
N
N
I
I
N
N
L
L
430
|
F
F
D
D
Y
Y
T
T
D
D
T
T
L
L
V
V
S
S
G
G
440
|
K
K
M
M
A
A
L
L
N
N
L
L
W
W
P
P
V
V
P
P
450
|
H
H
G
G
L
L
E
E
D
D
L
L
L
L
N
N
P
P
I
I
460
|
G
G
V
V
T
T
G
G
S
S
N
N
P
P
N
N
K
K
E
E
470
|
T
T
P
P
C
C
L
L
E
E
L
L
E
E
F
F
D
D
W
W
480
|
F
F
S
S
S
S
V
V
V
V
K
K
F
F
P
P
D
D
M
M
490
|
S
S
V
V
I
I
E
E
E
E
H
H
A
A
N
N
W
W
S
S
500
|
V
V
S
S
R
R
E
E
A
A
G
G
F
F
S
S
Y
Y
S
S
510
|
H
H
A
A
G
G
L
L
S
S
N
N
R
R
L
L
A
A
R
R
520
|
D
D
N
N
E
E
L
L
R
R
E
E
N
N
D
D
K
K
E
E
530
|
Q
Q
L
L
K
K
A
A
I
I
S
S
T
T
R
R
D
D
P
P
540
|
L
L
S
S
E
E
I
I
T
T
E
E
Q
Q
E
E
K
K
D
D
550
|
F
F
L
L
W
W
S
S
H
H
R
R
H
H
Y
Y
C
C
V
V
560
|
T
T
I
I
P
P
E
E
I
I
L
L
P
P
K
K
L
L
L
L
570
|
L
L
S
S
V
V
K
K
W
W
N
N
S
S
R
R
D
D
E
E
580
|
V
V
A
A
Q
Q
M
M
Y
Y
C
C
L
L
V
V
K
K
D
D
590
|
W
W
P
P
P
P
I
I
K
K
P
P
E
E
Q
Q
A
A
M
M
600
|
E
E
L
L
L
L
D
D
C
C
N
N
Y
Y
P
P
D
D
P
P
610
|
M
M
V
V
R
R
G
G
F
F
A
A
V
V
R
R
C
C
L
L
620
|
E
E
K
K
Y
Y
L
L
T
T
D
D
D
D
K
K
L
L
S
S
630
|
Q
Q
Y
Y
L
L
I
I
Q
Q
L
L
V
V
Q
Q
V
V
L
L
640
|
K
K
Y
Y
E
E
Q
Q
Y
Y
L
L
D
D
N
N
L
L
L
L
650
|
V
V
R
R
F
F
L
L
L
L
K
K
K
K
A
A
L
L
T
T
660
|
N
N
Q
Q
R
R
I
I
G
G
H
H
F
F
F
F
F
F
W
W
670
|
H
H
L
L
K
K
S
S
E
E
M
M
H
H
N
N
K
K
T
T
680
|
V
V
S
S
Q
Q
R
R
F
F
G
G
L
L
L
L
L
L
E
E
690
|
S
S
Y
Y
C
C
R
R
A
A
C
C
G
G
M
M
Y
Y
L
L
700
|
K
K
H
H
L
L
N
N
R
R
Q
Q
V
V
E
E
A
A
M
M
710
|
E
E
K
K
L
L
I
I
N
N
L
L
T
T
D
D
I
I
L
L
720
|
K
K
Q
Q
E
E
K
K
K
K
D
D
E
E
T
T
Q
Q
K
K
730
|
V
V
Q
Q
M
M
K
K
F
F
L
L
V
V
E
E
Q
Q
M
M
740
|
R
R
R
R
P
P
D
D
F
F
M
M
D
D
A
A
L
L
Q
Q
750
|
G
G
F
F
L
L
S
S
P
P
L
L
N
N
P
P
A
A
H
H
760
|
Q
Q
L
L
G
G
N
N
L
L
R
R
L
L
E
E
E
E
C
C
770
|
R
R
I
I
M
M
S
S
S
S
A
A
K
K
R
R
P
P
L
L
780
|
W
W
L
L
N
N
W
W
E
E
N
N
P
P
D
D
I
I
M
M
790
|
S
S
E
E
L
L
L
L
F
F
Q
Q
N
N
N
N
E
E
I
I
800
|
I
I
F
F
K
K
N
N
G
G
D
D
D
D
L
L
R
R
Q
Q
810
|
D
D
M
M
L
L
T
T
L
L
Q
Q
I
I
I
I
R
R
I
I
820
|
M
M
E
E
N
N
I
I
W
W
Q
Q
N
N
Q
Q
G
G
L
L
830
|
D
D
L
L
R
R
M
M
L
L
P
P
Y
Y
G
G
C
C
L
L
840
|
S
S
I
I
G
G
D
D
C
C
V
V
G
G
L
L
I
I
E
E
850
|
V
V
V
V
R
R
N
N
S
S
H
H
T
T
I
I
M
M
Q
Q
860
|
I
I
Q
Q
C
C
K
K
G
G
G
G
L
L
K
K
G
G
A
A
870
|
L
L
Q
Q
F
F
N
N
S
S
H
H
T
T
L
L
H
H
Q
Q
880
|
W
W
L
L
K
K
D
D
K
K
N
N
K
K
G
G
E
E
I
I
890
|
Y
Y
D
D
A
A
A
A
I
I
D
D
L
L
F
F
T
T
R
R
900
|
S
S
C
C
A
A
G
G
Y
Y
C
C
V
V
A
A
T
T
F
F
910
|
I
I
L
L
G
G
I
I
G
G
D
D
R
R
H
H
N
N
S
S
920
|
N
N
I
I
M
M
V
V
K
K
D
D
D
D
G
G
Q
Q
L
L
930
|
F
F
H
H
I
I
D
D
F
F
G
G
H
H
F
F
L
L
D
D
940
|
H
H
K
K
K
K
K
K
K
K
F
F
G
G
Y
Y
K
K
R
R
950
|
E
E
R
R
V
V
P
P
F
F
V
V
L
L
T
T
Q
Q
D
D
960
|
F
F
L
L
I
I
V
V
I
I
S
S
K
K
G
G
A
A
Q
Q
970
|
E
E
C
C
T
T
K
K
T
T
R
R
E
E
F
F
E
E
R
R
980
|
F
F
Q
Q
E
E
M
M
C
C
Y
Y
K
K
A
A
Y
Y
L
L
990
|
A
A
I
I
R
R
Q
Q
H
H
A
A
N
N
L
L
F
F
I
I
1000
|
N
N
L
L
F
F
S
S
M
M
M
M
L
L
G
G
S
S
G
G
1010
|
M
M
P
P
E
E
L
L
Q
Q
S
S
F
F
D
D
D
D
I
I
1020
|
A
A
Y
Y
I
I
R
R
K
K
T
T
L
L
A
A
L
L
D
D
1030
|
K
K
T
T
E
E
Q
Q
E
E
A
A
L
L
E
E
Y
Y
F
F
1040
|
M
M
K
K
Q
Q
M
M
N
N
D
D
A
A
H
R
H
H
G
G
1050
|
G
G
W
W
T
T
T
T
K
K
M
M
D
D
W
W
I
I
F
F
1060
|
H
H
T
T
I
I
K
K
Q
Q
H
H
A
A
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model SW1736 cells Thyroid Homo sapiens (Human) CVCL_3883
C643 cells Thyroid gland Homo sapiens (Human) CVCL_5969
HTH7 cells Thyroid gland Homo sapiens (Human) CVCL_6289
Hth74 cells Thyroid gland Homo sapiens (Human) CVCL_6288
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of MK2206 + Temsirolimus by unusual activation of pro-survival pathway
TAK-632
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) [17]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug TAK-632
 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 SW1736 cells Thyroid Homo sapiens (Human) CVCL_3883
8505C cells Thyroid Homo sapiens (Human) CVCL_1054
Hth104 cells Thyroid gland Homo sapiens (Human) CVCL_A427
In Vivo Model Mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of TAK-632 by aberration of the drug's therapeutic target
XMD15-44
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [14]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
Sensitive Drug XMD15-44
 Drug Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
L
T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model TT cells Thyroid gland Homo sapiens (Human) CVCL_1774
RET/V804M cells Bone marrow Mus musculus (Mouse) CVCL_XZ26
RET/V804L cells N.A. Mus musculus (Mouse) CVCL_XZ25
RET/S891A cells N.A. Homo sapiens (Human) N.A.
RET/M918T cells N.A. Homo sapiens (Human) N.A.
RET/M918T cells N.A. Homo sapiens (Human) N.A.
RET/L790F cells N.A. Homo sapiens (Human) N.A.
RET/E768D cells N.A. Homo sapiens (Human) N.A.
RET/C634R cells N.A. Homo sapiens (Human) N.A.
RET/C634R cells N.A. Homo sapiens (Human) N.A.
RET/A883F cells N.A. Homo sapiens (Human) N.A.
MZ-CRC-1 cells Pleural effusion Homo sapiens (Human) CVCL_A656
RET/V804M cells Bone marrow Mus musculus (Mouse) CVCL_XZ26
RET/E768D cells N.A. Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cell counting assay
Investigative Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Iodine-131
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) [8]
Resistant Disease Thyroid carcinoma [ICD-11: 2D10.4]
Resistant Drug Iodine-131
 Drug 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
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420
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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
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W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
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G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
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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
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P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
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N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
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H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
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S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
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Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
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H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
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M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
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T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
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K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
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N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
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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
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F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
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M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
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K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
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Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
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M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
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N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
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G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
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K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
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K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
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K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
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I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
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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
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
Epigenetic signaling pathway Activation hsa05207
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Low throughput experiment assay
Mechanism Description Primary resistance appears to develop early in tumorigenesis via genetic or epigenetic events that activate pro-proliferation pathways or inhibit pathways that stimulate cell death. Loss or gain of a cell surface receptor or transporter or other alterations in the drug target pathway can also lead to resistance against pharmacological agents, as described below for PTC with the BRAFV600E mutation. BRA FV600E 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. BRAF V600E PTC exhibits primary resistance to RAI treatment, higher rates of tumor recurrence and metastases, and lower survival rates.
References
Ref 1 The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cellsJ Clin Endocrinol Metab. 2011 Jun;96(6):E991-5. doi: 10.1210/jc.2010-2381. Epub 2011 Apr 6.
Ref 2 Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancerCancer. 2016 Dec 15;122(24):3856-3864. doi: 10.1002/cncr.30252. Epub 2016 Aug 15.
Ref 3 KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid CancerJ Natl Compr Canc Netw. 2019 May 1;17(5):409-413. doi: 10.6004/jnccn.2019.7292.
Ref 4 Precision Targeted Therapy with BLU-667 for RET-Driven CancersCancer Discov. 2018 Jul;8(7):836-849. doi: 10.1158/2159-8290.CD-18-0338. Epub 2018 Apr 15.
Ref 5 Selective RET kinase inhibition for patients with RET-altered cancersAnn Oncol. 2018 Aug 1;29(8):1869-1876. doi: 10.1093/annonc/mdy137.
Ref 6 Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid CancerJ Clin Oncol. 2018 Jan 1;36(1):7-13. doi: 10.1200/JCO.2017.73.6785. Epub 2017 Oct 26.
Ref 7 Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trialJ Clin Oncol. 2012 Jan 10;30(2):134-41. doi: 10.1200/JCO.2011.35.5040. Epub 2011 Oct 24.
Ref 8 Evolution of resistance to thyroid cancer therapy. Aging (Albany NY). 2016 Aug;8(8):1576-7. doi: 10.18632/aging.101030.
Ref 9 The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid CancerMol Cancer Ther. 2016 Aug;15(8):1952-63. doi: 10.1158/1535-7163.MCT-15-0702. Epub 2016 May 24.
Ref 10 AZD1480 blocks growth and tumorigenesis of RET- activated thyroid cancer cell linesPLoS One. 2012;7(10):e46869. doi: 10.1371/journal.pone.0046869. Epub 2012 Oct 2.
Ref 11 Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodineJ Clin Invest. 2016 Nov 1;126(11):4119-4124. doi: 10.1172/JCI89067. Epub 2016 Sep 26.
Ref 12 Genetic alterations in the phosphoinositide 3-kinase/Akt signaling pathway confer sensitivity of thyroid cancer cells to therapeutic targeting of Akt and mammalian target of rapamycinCancer Res. 2009 Sep 15;69(18):7311-9. doi: 10.1158/0008-5472.CAN-09-1077. Epub 2009 Aug 25.
Ref 13 Anti-tumor activity of motesanib in a medullary thyroid cancer modelJ Endocrinol Invest. 2012 Feb;35(2):181-90. doi: 10.3275/7609. Epub 2011 Mar 21.
Ref 14 Identification of Novel Small Molecule Inhibitors of Oncogenic RET KinasePLoS One. 2015 Jun 5;10(6):e0128364. doi: 10.1371/journal.pone.0128364. eCollection 2015.
Ref 15 CLM3, a multitarget tyrosine kinase inhibitor with antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivoJ Clin Endocrinol Metab. 2014 Apr;99(4):E572-81. doi: 10.1210/jc.2013-2321. Epub 2014 Jan 1.
Ref 16 The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathwayJ Clin Endocrinol Metab. 2011 Apr;96(4):E577-85. doi: 10.1210/jc.2010-2644. Epub 2011 Feb 2.
Ref 17 An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF SignalingCancer Cell. 2016 Sep 12;30(3):485-498. doi: 10.1016/j.ccell.2016.06.024. Epub 2016 Aug 11.

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