Disease Information

General Information of the Disease (ID: DIS00226)
Name
Multiple endocrine neoplasia
ICD
ICD-11: 2F7A
Resistance Map
Type(s) of Resistant Mechanism of This Disease
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
4 drug(s) in total
Click to Show/Hide the Full List of Drugs
Cabozantinib
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) [1]
Resistant Disease Multiple endocrine neoplasia [ICD-11: 2F7A.0]
Resistant Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T
 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 BaF3 cells Bone Mus musculus (Mouse) CVCL_0161
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 LC50 assay
Mechanism Description M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.
Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]
Resistant Disease Multiple endocrine neoplasia [ICD-11: 2F7A.0]
Resistant Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T
 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 BaF3 cells Bone Mus musculus (Mouse) CVCL_0161
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 LC50 assay
Mechanism Description M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.
Intedanib
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) [1]
Resistant Disease Multiple endocrine neoplasia [ICD-11: 2F7A.0]
Resistant Drug Intedanib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T
 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 BaF3 cells Bone Mus musculus (Mouse) CVCL_0161
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 LC50 assay
Mechanism Description M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.
Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]
Resistant Disease Multiple endocrine neoplasia [ICD-11: 2F7A.0]
Resistant Drug Intedanib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T
 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 BaF3 cells Bone Mus musculus (Mouse) CVCL_0161
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 LC50 assay
Mechanism Description M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.
Lenvatinib
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]
Resistant Disease Multiple endocrine neoplasia [ICD-11: 2F7A.0]
Resistant Drug Lenvatinib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T
 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 BaF3 cells Bone Mus musculus (Mouse) CVCL_0161
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 LC50 assay
Mechanism Description M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.
Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]
Resistant Disease Multiple endocrine neoplasia [ICD-11: 2F7A.0]
Resistant Drug Lenvatinib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T
 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 BaF3 cells Bone Mus musculus (Mouse) CVCL_0161
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 LC50 assay
Mechanism Description M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.
Vandetanib
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]
Resistant Disease Multiple endocrine neoplasia [ICD-11: 2F7A.0]
Resistant Drug Vandetanib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T
 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 BaF3 cells Bone Mus musculus (Mouse) CVCL_0161
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 LC50 assay
Mechanism Description M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.
Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]
Resistant Disease Multiple endocrine neoplasia [ICD-11: 2F7A.0]
Resistant Drug Vandetanib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T
 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 BaF3 cells Bone Mus musculus (Mouse) CVCL_0161
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 LC50 assay
Mechanism Description M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.
References
Ref 1 Drug resistance profiles of mutations in the RET kinase domain .Br J Pharmacol. 2018 Sep;175(17):3504-3515. doi: 10.1111/bph.14395. Epub 2018 Jul 19. 10.1111/bph.14395

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