Drug Information

Drug (ID: DG00144) and It's Reported Resistant Information
Name
Imatinib
Synonyms
Cgp 57148; Glamox; Glamox (TN); Gleevec (TN); Glivec (TN); Imatinib (INN); Imatinib (STI571); Imatinib Methansulfonate; Imatinib [INN:BAN]; 112GI019; 152459-95-5; BKJ8M8G5HI; CCRIS 9076; CGP-57148; CHEMBL941; Imatinib free base; STI; UNII-BKJ8M8G5HI
    Click to Show/Hide
Indication
In total 5 Indication(s)
Mature B-cell lymphoma [ICD-11: 2A85]
Approved
[1]
Myeloproliferative neoplasm [ICD-11: 2A22]
Approved
[1]
Malignant intestine neoplasm [ICD-11: 2C0Z]
Phase 3
[1]
Lung cancer [ICD-11: 2C25]
Phase 2
[1]
Mastocytosis [ICD-11: 2A21]
Investigative
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (10 diseases)
Acute lymphocytic leukemia [ICD-11: 2B33]
[2]
Atypical chronic myeloid leukemia [ICD-11: 2A41]
[3]
Brain cancer [ICD-11: 2A00]
[4]
Breast cancer [ICD-11: 2C60]
[5]
Chronic myeloid leukemia [ICD-11: 2A20]
[2], [6], [7]
Dermatofibrosarcoma protuberans [ICD-11: 2B53]
[8]
Gastrointestinal cancer [ICD-11: 2B5B]
[9], [10], [11]
Gastrointestinal stromal tumor [ICD-11: 2B5B]
[12]
Kidney cancer [ICD-11: 2C90]
[13]
Metastatic liver cancer [ICD-11: 2D80]
[14]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (3 diseases)
Neuroblastoma [ICD-11: 2A00]
[15]
Chronic myeloid leukemia [ICD-11: 2A20]
[16]
Gastrointestinal cancer [ICD-11: 2B5B]
[17]
Target Fusion protein Bcr-Abl (Bcr-Abl) BCR_HUMAN-ABL1_HUMAN [1]
Mcl-1 messenger RNA (MCL-1 mRNA) MCL1_HUMAN [1]
Platelet-derived growth factor receptor (PDGFR) NOUNIPROTAC [1]
Tyrosine-protein kinase Kit (KIT) KIT_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C29H31N7O
IsoSMILES
CC1=C(C=C(C=C1)NC(=O)C2=CC=C(C=C2)CN3CCN(CC3)C)NC4=NC=CC(=N4)C5=CN=CC=C5
InChI
1S/C29H31N7O/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34)
InChIKey
KTUFNOKKBVMGRW-UHFFFAOYSA-N
PubChem CID
5291
ChEBI ID
CHEBI:45783
TTD Drug ID
D0AZ3C
VARIDT ID
DR00032
DrugBank ID
DB00619
Type(s) of Resistant Mechanism of This Drug due to Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Chronic myeloid leukemia [ICD-11: 2A20]
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) [18], [19]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease 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
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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) [6], [7], [20]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease 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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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) [6], [7], [20]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease 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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-
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) [21], [22]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease 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.
Acute lymphocytic leukemia [ICD-11: 2B33]
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) [2], [23]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease 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 Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 CR-Abl sequencing assay
Experiment for
Drug Resistance		 Event-free survival assay
Mechanism Description M244V and H396 mutations have been shown to be more resistant to imatinib but both have been shown to be sensitive to second generation TkI's such as nilotinib and dasatinib.
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [2]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease 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
Mechanism Description Different mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease. In summary, binding of STI571 to BCR-ABL depends on a number of specific interactions within the ATPbinding site. Our results strongly suggest that a patient could be resistant to STI571 by acquisition of different individual point mutations within the ATP-binding pocket or activation loop of BCR-ABL, even though the number of mutations might be limited. This factor could make it difficult to overcome resistance to STI571 by use of alternative kinase inhibitors.
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [24]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease 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		 PCR-Invader assay; Direct sequencing assay
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description The PCR-Invader assay used in this study is an appropriate tool for the screening of mutations during TkI therapy. High Sokal score is only predictive factor for emergence of mutation in CML-CP. P-loop mutations were associated with poor PFS in CML-CP.
Gastrointestinal cancer [ICD-11: 2B5B]
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: Mast/stem cell growth factor receptor Kit (KIT) [11], [25], [26]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Molecule Alteration Missense mutation
p.T670I
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.25  Å
PDB: 6HH1
Mutant Type Structure Method: X-ray diffraction Resolution: 2.40  Å
PDB: 8PQG
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.88
TM score: 0.9084
Amino acid change:
T670I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
G
-
S
550
|
-
M
-
P
-
M
-
Y
-
E
-
V
-
Q
-
W
-
K
-
V
560
|
-
V
-
E
-
E
-
S
-
N
G
G
N
N
N
N
Y
Y
V
S
570
|
Y
Y
I
I
D
D
P
P
T
T
Q
Q
L
L
P
P
Y
Y
D
D
580
|
H
H
K
K
W
W
E
E
F
F
P
P
R
R
N
N
R
R
L
L
590
|
S
S
F
F
G
G
K
K
T
T
L
L
G
G
A
A
G
G
A
A
600
|
F
F
G
G
K
K
V
V
V
V
E
E
A
A
T
T
A
A
Y
Q
610
|
G
G
L
L
I
I
K
K
S
S
D
D
A
A
A
A
M
M
T
T
620
|
V
V
A
A
V
V
K
K
M
M
L
L
K
K
P
P
S
S
A
A
630
|
H
H
L
S
T
T
E
E
R
R
E
E
A
A
L
L
M
M
S
S
640
|
E
E
L
L
K
K
V
V
L
L
S
S
Y
Y
L
L
G
G
N
N
650
|
H
H
M
E
N
N
I
I
V
V
N
N
L
L
L
L
G
G
A
A
660
|
C
C
T
T
I
H
G
G
G
G
P
P
T
T
L
L
V
V
I
I
670
|
T
I
E
E
Y
Y
C
C
C
C
Y
Y
G
G
D
D
L
L
L
L
680
|
N
N
F
F
L
L
R
R
R
R
K
K
R
R
D
D
S
E
F
F
690
|
I
V
C
P
S
Y
K
K
T
-
-
-
-
-
-
-
-
-
-
-
700
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
710
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
720
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
730
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
740
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
750
|
-
-
-
-
-
-
S
-
P
V
A
A
I
P
-
E
-
D
-
L
760
|
-
Y
E
K
L
D
A
F
L
L
D
T
L
L
E
E
D
H
L
L
770
|
L
L
S
S
F
F
S
S
Y
Y
Q
Q
V
V
A
A
K
K
G
G
780
|
M
M
A
A
F
F
L
L
A
A
S
S
K
K
N
N
C
C
I
I
790
|
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
I
I
L
L
800
|
L
L
T
T
H
H
G
G
R
N
I
I
T
T
K
K
I
I
C
C
810
|
D
D
F
F
G
G
L
L
A
A
R
R
D
D
I
I
K
K
N
N
820
|
D
D
S
S
N
N
Y
Y
V
V
V
D
K
K
G
G
N
N
A
A
830
|
R
R
L
L
P
P
V
V
K
K
W
W
M
M
A
A
P
P
E
E
840
|
S
S
I
I
F
F
N
N
C
S
V
V
Y
Y
T
T
F
F
E
E
850
|
S
S
D
D
V
V
W
W
S
S
Y
Y
G
G
I
I
F
F
L
L
860
|
W
W
E
E
L
L
F
F
S
S
L
L
G
G
S
S
S
S
P
P
870
|
Y
Y
P
P
G
G
M
M
P
P
V
V
D
D
S
S
K
K
F
F
880
|
Y
Y
K
K
M
M
I
I
K
K
E
E
G
G
F
F
R
R
M
M
890
|
L
S
S
S
P
P
E
E
H
Y
A
A
P
P
A
A
E
E
M
M
900
|
Y
Y
D
D
I
I
M
M
K
K
T
T
C
C
W
W
D
D
A
A
910
|
D
D
P
P
L
D
K
K
R
R
P
P
T
T
F
F
K
K
Q
Q
920
|
I
I
V
V
Q
Q
L
D
I
I
E
E
K
K
Q
Q
I
I
S
S
930
|
-
E
-
S
-
T
-
N
-
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST882 cells Gastric Homo sapiens (Human) CVCL_7044
293T cells Breast Homo sapiens (Human) CVCL_0063
GIST48 cells Gastric Homo sapiens (Human) CVCL_7041
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST430 cells Colon Homo sapiens (Human) CVCL_7040
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 In situ Cell Death Detection assay
Mechanism Description We show that bortezomib rapidly triggers apoptosis in GIST cells through a combination of mechanisms involving H2AX upregulation and loss of kIT protein expression. We demonstrate downregulation of kIT transcription as an underlying mechanism for bortezomib-mediated inhibition of kIT expression. Collectively, our results show that inhibition of the proteasome using bortezomib can effectively kill imatinib-sensitive and imatinib-resistant GIST cells in vitro and provide a rationale to test the efficacy of bortezomib in GIST patients. Bortezomib has a dual mode of action against GIST cells involving upregulation of pro-apoptotic histone H2AX and downregulation of oncogenic kIT.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [27]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Molecule Alteration Missense mutation
p.V600E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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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 RAS/RAF/Mek/ERK signaling pathway Activation hsa04010
Experiment for
Molecule Alteration		 Direct sequencing assay
Experiment for
Drug Resistance		 High-performance liquid chromatography screening assay
Mechanism Description This finding, in combination with the loss of kIT expression, suggests the possibility of activation of RAS-RAF-MEk-ERk pathways driven by a kIT-independent oncogenic mechanism. Most mutations lie within the kinase domain with a single nucleotide substitution at position 1799 in exon 15, leading to the V600E amino-acid substitution (98 %).
References
Ref 1 Downregulation of lncRNA CCDC26 contributes to imatinib resistance in human gastrointestinal stromal tumors through IGF-1R upregulation. Braz J Med Biol Res. 2019;52(6):e8399. doi: 10.1590/1414-431x20198399. Epub 2019 Jun 3.
Ref 2 BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet. 2002 Feb 9;359(9305):487-91. doi: 10.1016/S0140-6736(02)07679-1.
Ref 3 Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic optionsDrug Discov Today. 2019 Jul;24(7):1355-1369. doi: 10.1016/j.drudis.2019.05.007. Epub 2019 May 15.
Ref 4 MiR-203 downregulation is responsible for chemoresistance in human glioblastoma by promoting epithelial-mesenchymal transition via SNAI2. Oncotarget. 2015 Apr 20;6(11):8914-28. doi: 10.18632/oncotarget.3563.
Ref 5 Circulating-free DNA Mutation Associated with Response of Targeted Therapy in Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer. Chin Med J (Engl). 2017 Mar 5;130(5):522-529. doi: 10.4103/0366-6999.200542.
Ref 6 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 7 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 8 Genetic aberrations in imatinib-resistant dermatofibrosarcoma protuberans revealed by whole genome sequencing .PLoS One. 2013 Jul 29;8(7):e69752. doi: 10.1371/journal.pone.0069752. Print 2013. 10.1371/journal.pone.0069752
Ref 9 Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology. 2003 Sep;125(3):660-7. doi: 10.1016/s0016-5085(03)01046-1.
Ref 10 Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-9. doi: 10.1200/JCO.2003.04.190.
Ref 11 Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology. 2005 Feb;128(2):270-9. doi: 10.1053/j.gastro.2004.11.020.
Ref 12 The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomasMol Cancer Ther. 2013 Oct;12(10):1994-2005. doi: 10.1158/1535-7163.MCT-13-0206. Epub 2013 Jul 19.
Ref 13 Management of metastatic gastrointestinal stromal tumour in the Glivec era: a practical case-based approach .Intern Med J. 2006 Jun;36(6):367-77. doi: 10.1111/j.1445-5994.2006.01077.x. 10.1111/j.1445-5994.2006.01077.x
Ref 14 Spatial modelling of tumour drug resistance: the case of GIST liver metastases .Math Med Biol. 2017 Jun 1;34(2):151-176. doi: 10.1093/imammb/dqw002. 10.1093/imammb/dqw002
Ref 15 Protein kinase C inhibitor AEB071 targets ocular melanoma harboring GNAQ mutations via effects on the PKC/Erk1/2 and PKC/NF-kB pathwaysMol Cancer Ther. 2012 Sep;11(9):1905-14. doi: 10.1158/1535-7163.MCT-12-0121. Epub 2012 May 31.
Ref 16 MiR-34a attenuates paclitaxel-resistance of hormone-refractory prostate cancer PC3 cells through direct and indirect mechanisms. Prostate. 2010 Oct 1;70(14):1501-12. doi: 10.1002/pros.21185.
Ref 17 CCDC26 knockdown enhances resistance of gastrointestinal stromal tumor cells to imatinib by interacting with c-KIT. Am J Transl Res. 2018 Jan 15;10(1):274-282. eCollection 2018.
Ref 18 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 19 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 20 Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002 Nov;16(11):2190-6. doi: 10.1038/sj.leu.2402741.
Ref 21 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 22 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 23 Imatinib resistant BCR-ABL1 mutations at relapse in children with Ph+ ALL: a Children's Oncology Group (COG) study. Br J Haematol. 2012 May;157(4):507-10. doi: 10.1111/j.1365-2141.2012.09039.x. Epub 2012 Feb 2.
Ref 24 BCR-ABL1 mutations in patients with imatinib-resistant Philadelphia chromosome-positive leukemia by use of the PCR-Invader assay. Leuk Res. 2011 May;35(5):598-603. doi: 10.1016/j.leukres.2010.12.006. Epub 2011 Jan 15.
Ref 25 Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005 Jun 1;11(11):4182-90. doi: 10.1158/1078-0432.CCR-04-2245.
Ref 26 Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res. 2006 Mar 15;12(6):1743-9. doi: 10.1158/1078-0432.CCR-05-1211.
Ref 27 KIT and BRAF heterogeneous mutations in gastrointestinal stromal tumors after secondary imatinib resistance. Gastric Cancer. 2015 Oct;18(4):796-802. doi: 10.1007/s10120-014-0414-7. Epub 2014 Aug 15.

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