Disease Information

General Information of the Disease (ID: DIS00065)
Name
Gastrointestinal cancer
ICD
ICD-11: 2B5B
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)
3 drug(s) in total
Click to Show/Hide the Full List of Drugs
Avapritinib
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) [1]
Resistant Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
Resistant Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.T670I (c.2009C>T)
 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 Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
M230 cells Skin Homo sapiens (Human) CVCL_D749
Experiment for
Molecule Alteration		 PCR
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
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: Mast/stem cell growth factor receptor Kit (KIT) [2], [3], [4]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
Resistant Drug Imatinib
 Drug 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) [5]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
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 %).
Regorafenib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [6]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.T670I (c.2009C>T)
 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
References
Ref 1 ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17-Mutant KITCancer Res. 2019 Aug 15;79(16):4283-4292. doi: 10.1158/0008-5472.CAN-18-3139. Epub 2019 Jul 3.
Ref 2 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 3 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 4 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 5 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.
Ref 6 Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trialLancet. 2006 Oct 14;368(9544):1329-38. doi: 10.1016/S0140-6736(06)69446-4.

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