Disease Information

General Information of the Disease (ID: DIS00050)
Name
Chronic myeloid leukemia
ICD
ICD-11: 2A20
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)
5 drug(s) in total
Click to Show/Hide the Full List of Drugs
Bosutinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [1], [2]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Bosutinib
 Drug Info 
Molecule Alteration Missense mutation
p.G12V
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.98  Å
PDB: 7SCW
Mutant Type Structure Method: X-ray diffraction Resolution: 1.96  Å
PDB: 7SCX
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.47
TM score: 0.99104
Amino acid change:
G12V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
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
V
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
S
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
170
|
M
M
S
S
K
K
D
D
G
G
K
K
K
K
K
K
K
K
K
K
180
|
K
K
S
S
K
K
T
T
K
K
C
C
V
V
I
I
M
M
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation JAKT2/STAT signaling pathway Activation hsa04030
RAF/KRAS/MEK signaling pathway Activation hsa04010
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
U937 cells Blood Homo sapiens (Human) CVCL_0007
K562 cells Blood Homo sapiens (Human) CVCL_0004
KCL-22 cells Bone marrow Homo sapiens (Human) CVCL_2091
Sup-B15 cells Bone marrow Homo sapiens (Human) CVCL_0103
HEL cells Blood Homo sapiens (Human) CVCL_0001
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Sanger Sequencing assay
Mechanism Description This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.
Dasatinib
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: Tyrosine-protein kinase ABL1 (ABL1) [3], [4], [5]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Dasatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
G
-
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
50
|
-
R
-
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
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		 Direct sequencing assay; Sanger sequencing assay
Mechanism Description For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [3], [4], [6]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Dasatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G250E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
60
|
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
-
R
-
70
|
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
-
G
-
80
|
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
-
K
-
90
|
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
-
N
-
100
|
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
-
D
-
110
|
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
-
S
-
120
|
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
-
L
-
130
|
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
-
E
-
140
|
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
-
V
-
150
|
P
-
S
-
N
-
Y
-
I
-
T
-
P
-
V
-
N
-
S
-
160
|
L
-
E
-
K
-
H
-
S
-
W
-
Y
-
H
-
G
-
P
-
170
|
V
-
S
-
R
-
N
-
A
-
A
-
E
-
Y
-
L
-
L
-
180
|
S
-
S
-
G
-
I
-
N
-
G
-
S
-
F
-
L
-
V
-
190
|
R
-
E
-
S
-
E
-
S
-
S
-
P
-
G
-
Q
-
R
-
200
|
S
-
I
-
S
-
L
-
R
-
Y
-
E
-
G
-
R
-
V
-
210
|
Y
-
H
-
Y
-
R
-
I
-
N
-
T
-
A
-
S
-
D
-
220
|
G
-
K
-
L
-
Y
-
V
-
S
-
S
-
E
-
S
-
R
-
230
|
F
-
N
-
T
-
L
-
A
-
E
-
L
-
V
-
H
-
H
-
240
|
H
-
S
-
T
-
V
-
A
-
D
-
G
-
L
-
I
-
T
-
250
|
T
-
L
-
H
-
Y
-
P
-
A
-
P
-
K
-
R
-
N
-
260
|
K
-
P
-
T
-
V
-
Y
-
G
-
V
-
S
S
P
P
N
N
270
|
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
D
D
280
|
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
E
G
G
290
|
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
W
W
300
|
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
K
K
310
|
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
E
E
320
|
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
L
K
K
330
|
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
L
L
340
|
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
F
F
350
|
Y
Y
I
I
I
I
I
T
E
E
F
F
M
M
T
T
Y
Y
G
G
360
|
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
N
N
370
|
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
L
L
380
|
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
M
M
390
|
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
H
H
400
|
R
R
N
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
410
|
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
D
D
420
|
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
Y
G
G
D
D
430
|
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
F
F
440
|
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
L
L
450
|
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
D
D
460
|
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
E
E
470
|
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
P
P
480
|
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
L
L
490
|
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
P
P
500
|
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
L
L
510
|
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
S
S
520
|
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
Q
Q
530
|
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
S
S
540
|
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
G
G
550
|
K
K
Q
Q
G
G
V
V
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		 Direct sequencing assay; Sanger sequencing assay
Mechanism Description For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [1], [2]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Dasatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G12V
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.98  Å
PDB: 7SCW
Mutant Type Structure Method: X-ray diffraction Resolution: 1.96  Å
PDB: 7SCX
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.47
TM score: 0.99104
Amino acid change:
G12V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
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
V
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
S
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
170
|
M
M
S
S
K
K
D
D
G
G
K
K
K
K
K
K
K
K
K
K
180
|
K
K
S
S
K
K
T
T
K
K
C
C
V
V
I
I
M
M
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation JAKT2/STAT signaling pathway Activation hsa04030
RAF/KRAS/MEK signaling pathway Activation hsa04010
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
U937 cells Blood Homo sapiens (Human) CVCL_0007
K562 cells Blood Homo sapiens (Human) CVCL_0004
KCL-22 cells Bone marrow Homo sapiens (Human) CVCL_2091
Sup-B15 cells Bone marrow Homo sapiens (Human) CVCL_0103
HEL cells Blood Homo sapiens (Human) CVCL_0001
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Sanger Sequencing assay
Mechanism Description This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.
Imatinib
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: Tyrosine-protein kinase ABL1 (ABL1) [7], [8]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.H396P
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 4WA9
Mutant Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2G2H
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.35
TM score: 0.96269
Amino acid change:
H396P
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
S
-
230
|
P
-
N
-
Y
-
D
-
K
-
W
-
E
-
M
-
E
-
R
-
240
|
T
-
D
-
I
-
T
-
M
-
K
G
H
H
K
M
L
S
G
P
250
|
G
N
G
Y
Q
D
Y
K
G
W
E
E
V
M
Y
E
E
R
G
T
260
|
V
D
W
I
K
T
K
M
Y
K
S
H
L
K
T
L
V
G
A
G
270
|
V
G
K
Q
T
Y
L
G
K
E
E
V
D
Y
T
E
M
G
E
V
280
|
V
W
E
K
E
K
F
Y
L
S
K
L
E
T
A
V
A
A
V
V
290
|
M
K
K
T
E
L
I
K
K
E
H
D
P
T
N
M
L
E
V
V
300
|
Q
E
L
E
L
F
G
L
V
K
C
E
T
A
R
A
E
V
P
M
310
|
P
K
F
E
Y
I
I
K
I
H
T
P
E
N
F
L
M
V
T
Q
320
|
Y
L
G
L
N
G
L
V
L
C
D
T
Y
R
L
E
R
P
E
P
330
|
C
F
N
Y
R
I
Q
I
E
T
V
E
N
F
A
M
V
T
V
Y
340
|
L
G
L
N
Y
L
M
L
A
D
T
Y
Q
L
I
R
S
E
S
C
350
|
A
N
M
R
E
Q
Y
E
L
V
E
N
K
A
K
V
N
V
F
L
360
|
I
L
H
Y
R
M
D
A
L
T
A
Q
A
I
R
S
N
S
C
A
370
|
L
M
V
E
G
Y
E
L
N
E
H
K
L
K
V
N
K
F
V
I
380
|
A
H
D
R
F
D
G
L
L
A
S
A
R
R
L
N
M
C
T
L
390
|
G
V
D
G
T
E
Y
N
T
H
A
L
H
V
A
K
G
V
A
A
400
|
K
D
F
F
P
G
I
L
K
S
W
R
T
L
A
M
P
T
E
G
410
|
S
D
L
T
A
Y
Y
T
N
A
K
P
F
A
S
G
I
A
K
K
420
|
S
F
D
P
V
I
W
K
A
W
F
T
G
A
V
P
L
E
L
S
430
|
W
L
E
A
I
Y
A
N
T
K
Y
F
G
S
M
I
S
K
P
S
440
|
Y
D
P
V
G
W
I
A
D
F
L
G
S
V
Q
L
V
L
Y
W
450
|
E
E
L
I
L
A
E
T
K
Y
D
G
Y
M
R
S
M
P
E
Y
460
|
R
P
P
G
E
I
G
D
C
L
P
S
E
Q
K
V
V
Y
Y
E
470
|
E
L
L
L
M
E
R
K
A
D
C
Y
W
R
Q
M
W
E
N
R
480
|
P
P
S
E
D
G
R
C
P
P
S
E
F
K
A
V
E
Y
I
E
490
|
H
L
Q
M
A
R
F
A
E
C
T
W
M
Q
F
W
Q
N
E
P
500
|
S
S
S
D
I
R
S
P
D
S
E
F
V
A
E
E
K
I
E
H
510
|
L
Q
G
A
K
F
-
E
-
T
-
M
-
F
-
Q
-
E
-
S
520
|
-
S
-
I
-
S
-
D
-
E
-
V
-
E
-
K
-
E
-
L
530
|
-
G
-
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Peripheral blood Blood Homo sapiens (Human) N.A.
Bone marrow Blood Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Pyrosequencing analysis
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (kDMs).
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [9], [10], [11]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
G
-
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
50
|
-
R
-
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Peripheral blood Blood Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay; Allele-specific (AS)-RT-PCR assay
Mechanism Description We herein describe the development of a rapid allele-specific (AS)-RT-PCR assay to identify the T315I mutation, which confers full resistance to all available tyrosine-kinase inhibitors (TkI).
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [9], [10], [11]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G250E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
60
|
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
-
R
-
70
|
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
-
G
-
80
|
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
-
K
-
90
|
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
-
N
-
100
|
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
-
D
-
110
|
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
-
S
-
120
|
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
-
L
-
130
|
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
-
E
-
140
|
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
-
V
-
150
|
P
-
S
-
N
-
Y
-
I
-
T
-
P
-
V
-
N
-
S
-
160
|
L
-
E
-
K
-
H
-
S
-
W
-
Y
-
H
-
G
-
P
-
170
|
V
-
S
-
R
-
N
-
A
-
A
-
E
-
Y
-
L
-
L
-
180
|
S
-
S
-
G
-
I
-
N
-
G
-
S
-
F
-
L
-
V
-
190
|
R
-
E
-
S
-
E
-
S
-
S
-
P
-
G
-
Q
-
R
-
200
|
S
-
I
-
S
-
L
-
R
-
Y
-
E
-
G
-
R
-
V
-
210
|
Y
-
H
-
Y
-
R
-
I
-
N
-
T
-
A
-
S
-
D
-
220
|
G
-
K
-
L
-
Y
-
V
-
S
-
S
-
E
-
S
-
R
-
230
|
F
-
N
-
T
-
L
-
A
-
E
-
L
-
V
-
H
-
H
-
240
|
H
-
S
-
T
-
V
-
A
-
D
-
G
-
L
-
I
-
T
-
250
|
T
-
L
-
H
-
Y
-
P
-
A
-
P
-
K
-
R
-
N
-
260
|
K
-
P
-
T
-
V
-
Y
-
G
-
V
-
S
S
P
P
N
N
270
|
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
D
D
280
|
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
E
G
G
290
|
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
W
W
300
|
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
K
K
310
|
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
E
E
320
|
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
L
K
K
330
|
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
L
L
340
|
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
F
F
350
|
Y
Y
I
I
I
I
I
T
E
E
F
F
M
M
T
T
Y
Y
G
G
360
|
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
N
N
370
|
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
L
L
380
|
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
M
M
390
|
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
H
H
400
|
R
R
N
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
410
|
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
D
D
420
|
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
Y
G
G
D
D
430
|
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
F
F
440
|
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
L
L
450
|
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
D
D
460
|
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
E
E
470
|
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
P
P
480
|
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
L
L
490
|
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
P
P
500
|
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
L
L
510
|
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
S
S
520
|
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
Q
Q
530
|
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
S
S
540
|
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
G
G
550
|
K
K
Q
Q
G
G
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Peripheral blood Blood Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay
Mechanism Description Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [1], [2]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G12V
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.98  Å
PDB: 7SCW
Mutant Type Structure Method: X-ray diffraction Resolution: 1.96  Å
PDB: 7SCX
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.47
TM score: 0.99104
Amino acid change:
G12V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
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
V
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
S
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
170
|
M
M
S
S
K
K
D
D
G
G
K
K
K
K
K
K
K
K
K
K
180
|
K
K
S
S
K
K
T
T
K
K
C
C
V
V
I
I
M
M
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation JAKT2/STAT signaling pathway Activation hsa04030
RAF/KRAS/MEK signaling pathway Activation hsa04010
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
U937 cells Blood Homo sapiens (Human) CVCL_0007
K562 cells Blood Homo sapiens (Human) CVCL_0004
KCL-22 cells Bone marrow Homo sapiens (Human) CVCL_2091
Sup-B15 cells Bone marrow Homo sapiens (Human) CVCL_0103
HEL cells Blood Homo sapiens (Human) CVCL_0001
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Sanger Sequencing assay
Mechanism Description This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.
Nilotinib
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: Tyrosine-protein kinase ABL1 (ABL1) [12], [13]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Nilotinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
G
-
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
50
|
-
R
-
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
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		 Direct sequencing assay
Mechanism Description Our finding reflects the natural development of a T315I mutation within the hematopoietic system of the reported patient and indicates the importance of BCR-ABL1 mutation monitoring in more primitive cell populations. Considering the natural history of T315I development in this reported CML case, we hypothesize that BCR-ABL1 kD mutations may be pre-concentrated in more primitive CML cells, which subsequently expand into the PB.
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [5], [6], [12]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Nilotinib
 Drug Info 
Molecule Alteration Missense mutation
p.G250E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
60
|
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
-
R
-
70
|
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
-
G
-
80
|
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
-
K
-
90
|
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
-
N
-
100
|
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
-
D
-
110
|
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
-
S
-
120
|
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
-
L
-
130
|
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
-
E
-
140
|
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
-
V
-
150
|
P
-
S
-
N
-
Y
-
I
-
T
-
P
-
V
-
N
-
S
-
160
|
L
-
E
-
K
-
H
-
S
-
W
-
Y
-
H
-
G
-
P
-
170
|
V
-
S
-
R
-
N
-
A
-
A
-
E
-
Y
-
L
-
L
-
180
|
S
-
S
-
G
-
I
-
N
-
G
-
S
-
F
-
L
-
V
-
190
|
R
-
E
-
S
-
E
-
S
-
S
-
P
-
G
-
Q
-
R
-
200
|
S
-
I
-
S
-
L
-
R
-
Y
-
E
-
G
-
R
-
V
-
210
|
Y
-
H
-
Y
-
R
-
I
-
N
-
T
-
A
-
S
-
D
-
220
|
G
-
K
-
L
-
Y
-
V
-
S
-
S
-
E
-
S
-
R
-
230
|
F
-
N
-
T
-
L
-
A
-
E
-
L
-
V
-
H
-
H
-
240
|
H
-
S
-
T
-
V
-
A
-
D
-
G
-
L
-
I
-
T
-
250
|
T
-
L
-
H
-
Y
-
P
-
A
-
P
-
K
-
R
-
N
-
260
|
K
-
P
-
T
-
V
-
Y
-
G
-
V
-
S
S
P
P
N
N
270
|
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
D
D
280
|
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
E
G
G
290
|
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
W
W
300
|
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
K
K
310
|
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
E
E
320
|
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
L
K
K
330
|
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
L
L
340
|
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
F
F
350
|
Y
Y
I
I
I
I
I
T
E
E
F
F
M
M
T
T
Y
Y
G
G
360
|
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
N
N
370
|
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
L
L
380
|
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
M
M
390
|
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
H
H
400
|
R
R
N
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
410
|
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
D
D
420
|
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
Y
G
G
D
D
430
|
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
F
F
440
|
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
L
L
450
|
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
D
D
460
|
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
E
E
470
|
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
P
P
480
|
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
L
L
490
|
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
P
P
500
|
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
L
L
510
|
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
S
S
520
|
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
Q
Q
530
|
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
S
S
540
|
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
G
G
550
|
K
K
Q
Q
G
G
V
V
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		 RNA sequencing assay
Mechanism Description The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor (TkI) treatment. In addition to 9 point mutations (G250E / F317L, F359V, L387M, Y253H, M388L, M244V, T315I, D276G), 35 bp insertion between exons 8 and 9 and deletion exon 7 were detected. Our results demonstrate that direct sequencing is suitable for routine clinical monitoring patients with CML and may be useful for optimizing therapy.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [1], [2]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Nilotinib
 Drug Info 
Molecule Alteration Missense mutation
p.G12V
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.98  Å
PDB: 7SCW
Mutant Type Structure Method: X-ray diffraction Resolution: 1.96  Å
PDB: 7SCX
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.47
TM score: 0.99104
Amino acid change:
G12V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
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
V
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
S
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
170
|
M
M
S
S
K
K
D
D
G
G
K
K
K
K
K
K
K
K
K
K
180
|
K
K
S
S
K
K
T
T
K
K
C
C
V
V
I
I
M
M
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation JAKT2/STAT signaling pathway Activation hsa04030
RAF/KRAS/MEK signaling pathway Activation hsa04010
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
U937 cells Blood Homo sapiens (Human) CVCL_0007
K562 cells Blood Homo sapiens (Human) CVCL_0004
KCL-22 cells Bone marrow Homo sapiens (Human) CVCL_2091
Sup-B15 cells Bone marrow Homo sapiens (Human) CVCL_0103
HEL cells Blood Homo sapiens (Human) CVCL_0001
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Sanger Sequencing assay
Mechanism Description This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.
Ponatinib
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: Tyrosine-protein kinase ABL1 (ABL1) [14]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Ponatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
G
-
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
50
|
-
R
-
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
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		 Sanger sequencing assay
Mechanism Description Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations.
Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [14]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Ponatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G250E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
60
|
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
-
R
-
70
|
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
-
G
-
80
|
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
-
K
-
90
|
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
-
N
-
100
|
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
-
D
-
110
|
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
-
S
-
120
|
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
-
L
-
130
|
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
-
E
-
140
|
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
-
V
-
150
|
P
-
S
-
N
-
Y
-
I
-
T
-
P
-
V
-
N
-
S
-
160
|
L
-
E
-
K
-
H
-
S
-
W
-
Y
-
H
-
G
-
P
-
170
|
V
-
S
-
R
-
N
-
A
-
A
-
E
-
Y
-
L
-
L
-
180
|
S
-
S
-
G
-
I
-
N
-
G
-
S
-
F
-
L
-
V
-
190
|
R
-
E
-
S
-
E
-
S
-
S
-
P
-
G
-
Q
-
R
-
200
|
S
-
I
-
S
-
L
-
R
-
Y
-
E
-
G
-
R
-
V
-
210
|
Y
-
H
-
Y
-
R
-
I
-
N
-
T
-
A
-
S
-
D
-
220
|
G
-
K
-
L
-
Y
-
V
-
S
-
S
-
E
-
S
-
R
-
230
|
F
-
N
-
T
-
L
-
A
-
E
-
L
-
V
-
H
-
H
-
240
|
H
-
S
-
T
-
V
-
A
-
D
-
G
-
L
-
I
-
T
-
250
|
T
-
L
-
H
-
Y
-
P
-
A
-
P
-
K
-
R
-
N
-
260
|
K
-
P
-
T
-
V
-
Y
-
G
-
V
-
S
S
P
P
N
N
270
|
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
D
D
280
|
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
E
G
G
290
|
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
W
W
300
|
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
K
K
310
|
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
E
E
320
|
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
L
K
K
330
|
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
L
L
340
|
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
F
F
350
|
Y
Y
I
I
I
I
I
T
E
E
F
F
M
M
T
T
Y
Y
G
G
360
|
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
N
N
370
|
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
L
L
380
|
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
M
M
390
|
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
H
H
400
|
R
R
N
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
410
|
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
D
D
420
|
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
Y
G
G
D
D
430
|
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
F
F
440
|
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
L
L
450
|
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
D
D
460
|
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
E
E
470
|
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
P
P
480
|
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
L
L
490
|
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
P
P
500
|
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
L
L
510
|
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
S
S
520
|
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
Q
Q
530
|
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
S
S
540
|
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
G
G
550
|
K
K
Q
Q
G
G
V
V
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		 Sanger sequencing assay
Mechanism Description Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [1], [2]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Ponatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G12V
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.98  Å
PDB: 7SCW
Mutant Type Structure Method: X-ray diffraction Resolution: 1.96  Å
PDB: 7SCX
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.47
TM score: 0.99104
Amino acid change:
G12V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
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
V
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
S
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
170
|
M
M
S
S
K
K
D
D
G
G
K
K
K
K
K
K
K
K
K
K
180
|
K
K
S
S
K
K
T
T
K
K
C
C
V
V
I
I
M
M
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation JAKT2/STAT signaling pathway Activation hsa04030
RAF/KRAS/MEK signaling pathway Activation hsa04010
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
U937 cells Blood Homo sapiens (Human) CVCL_0007
K562 cells Blood Homo sapiens (Human) CVCL_0004
KCL-22 cells Bone marrow Homo sapiens (Human) CVCL_2091
Sup-B15 cells Bone marrow Homo sapiens (Human) CVCL_0103
HEL cells Blood Homo sapiens (Human) CVCL_0001
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Sanger Sequencing assay
Mechanism Description This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.
Investigative Drug(s)
1 drug(s) in total
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Tyrosine kinase inhibitor
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [15]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Tyrosine kinase inhibitor
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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160
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170
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210
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220
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230
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240
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250
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M
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T
260
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270
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Y
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280
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290
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Mechanism Description There are several identified mechanisms of resistance to TkIs. The presence of ABL kinase domain point mutation, which could be detected by molecular methods is one of them. ABL mutation was detected in 19 (31,6%) patients. In four cases with detected mutation the disease has progressed to blast crisis.
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [15]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
Resistant Drug Tyrosine kinase inhibitor
 Drug Info 
Molecule Alteration Missense mutation
p.G250E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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H
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E
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S
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E
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G
G
550
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K
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Q
Q
G
G
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Mechanism Description There are several identified mechanisms of resistance to TkIs. The presence of ABL kinase domain point mutation, which could be detected by molecular methods is one of them. ABL mutation was detected in 19 (31,6%) patients. In four cases with detected mutation the disease has progressed to blast crisis.
References
Ref 1 European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013 Aug 8;122(6):872-84. doi: 10.1182/blood-2013-05-501569. Epub 2013 Jun 26.
Ref 2 Dissecting Genomic Aberrations in Myeloproliferative Neoplasms by Multiplex-PCR and Next Generation Sequencing. PLoS One. 2015 Apr 20;10(4):e0123476. doi: 10.1371/journal.pone.0123476. eCollection 2015.
Ref 3 Longitudinal studies of SRC family kinases in imatinib- and dasatinib-resistant chronic myelogenous leukemia patients. Leuk Res. 2011 Jan;35(1):38-43. doi: 10.1016/j.leukres.2010.06.030. Epub 2010 Jul 29.
Ref 4 A novel insertion mutation of K294RGG within BCR-ABL kinase domain confers imatinib resistance: sequential analysis of the clonal evolution in a patient with chronic myeloid leukemia in blast crisis. Int J Hematol. 2011 Feb;93(2):237-242. doi: 10.1007/s12185-011-0766-2. Epub 2011 Jan 25.
Ref 5 Outcome of patients with chronic myeloid leukemia with multiple ABL1 kinase domain mutations receiving tyrosine kinase inhibitor therapy. Haematologica. 2011 Jun;96(6):918-21. doi: 10.3324/haematol.2010.039321. Epub 2011 Feb 28.
Ref 6 Complexity of BCR-ABL kinase domain mutations during the course of therapy with tyrosine kinase inhibitors in chronic myeloid leukemia. Am J Hematol. 2009 Apr;84(4):256-7. doi: 10.1002/ajh.21366.
Ref 7 Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib. Blood. 2009 Sep 24;114(13):2598-605. doi: 10.1182/blood-2008-08-173674. Epub 2009 Jul 22.
Ref 8 Increased genomic instability may contribute to the development of kinase domain mutations in chronic myeloid leukemia. Int J Hematol. 2014 Dec;100(6):567-74. doi: 10.1007/s12185-014-1685-9. Epub 2014 Oct 4.
Ref 9 High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002 May 1;99(9):3472-5. doi: 10.1182/blood.v99.9.3472.
Ref 10 Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002 Aug;2(2):117-25. doi: 10.1016/s1535-6108(02)00096-x.
Ref 11 Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002 Nov;16(11):2190-6. doi: 10.1038/sj.leu.2402741.
Ref 12 Use of direct sequencing for detection of mutations in the BCR-ABL kinase domain in Slovak patients with chronic myeloid leukemia. Neoplasma. 2011;58(6):548-53. doi: 10.4149/neo_2011_06_548.
Ref 13 Analysis of mutations in the BCR-ABL1 kinase domain, using direct sequencing: detection of the T315I mutation in bone marrow CD34+ cells of a patient with chronic myelogenous leukemia 6 months prior to its emergence in peripheral blood. Mol Diagn Ther. 2012 Jun 1;16(3):163-6. doi: 10.2165/11632420-000000000-00000.
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