Disease Information

General Information of the Disease (ID: DIS00073)
Name
Colorectal cancer
ICD
ICD-11: 2B91
Resistance Map
Type(s) of Resistant Mechanism of This Disease with Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  DISM: Drug Inactivation by Structure Modification
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
6 drug(s) in total
Click to Show/Hide the Full List of Drugs
Cetuximab
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 KRas (KRAS) [1], [2], [3]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Cetuximab
 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 EGFR/RAS signaling pathway Activation hsa01521
In Vitro Model LIM1215 cells Colon Homo sapiens (Human) CVCL_2574
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy assay
Mechanism Description Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations (27780856). kRAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs).
Key Molecule: GTPase KRas (KRAS) [3]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Cetuximab
 Drug Info 
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.31  Å
PDB: 6T5V
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6MNX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.14
TM score: 0.96411
Amino acid change:
Q61H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
C
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
S
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
H
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
|
L
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
C
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
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		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy assay
Mechanism Description Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.
Key Molecule: GTPase KRas (KRAS) [3]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Cetuximab
 Drug Info 
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 8JHL
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.9318
Amino acid change:
G12D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
D
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
C
C
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
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
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		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy assay
Mechanism Description Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Cetuximab
 Drug Info 
Molecule Alteration Missense mutation
p.V600E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Colon cells Colon Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy assay
Mechanism Description Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.
Dabrafenib/Trametinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [4]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Dabrafenib/Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Entrectinib
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: Tropomyosin-related kinase A (TrkA) [5]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Entrectinib
 Drug Info 
Molecule Alteration Missense mutation
p.G595R (c.1783G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5H3Q
Mutant Type Structure Method: X-ray diffraction Resolution: 2.09  Å
PDB: 8J5X
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.93325
Amino acid change:
G595R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
S
-
L
-
S
-
P
-
T
-
480
|
E
-
G
-
K
-
G
-
S
-
G
-
L
-
Q
-
G
-
H
-
490
|
I
-
I
-
E
-
N
-
P
-
Q
-
Y
-
F
-
S
S
D
D
500
|
A
A
C
C
V
V
H
H
H
H
I
I
K
K
R
R
R
R
D
D
510
|
I
I
V
V
L
L
K
K
W
W
E
E
L
L
G
G
E
E
G
G
520
|
A
A
F
F
G
G
K
K
V
V
F
F
L
L
A
A
E
E
C
C
530
|
H
H
N
N
L
L
L
L
P
P
E
E
Q
Q
D
D
K
K
M
M
540
|
L
L
V
V
A
A
V
V
K
K
A
A
L
L
K
K
E
E
A
A
550
|
S
S
E
E
S
S
A
A
R
R
Q
Q
D
D
F
F
Q
Q
R
R
560
|
E
E
A
A
E
E
L
L
L
L
T
T
M
M
L
L
Q
Q
H
H
570
|
Q
Q
H
H
I
I
V
V
R
R
F
F
F
F
G
G
V
V
C
C
580
|
T
T
E
E
G
G
R
R
P
P
L
L
L
L
M
M
V
V
F
F
590
|
E
E
Y
Y
M
M
R
R
H
H
G
R
D
D
L
L
N
N
R
R
600
|
F
F
L
L
R
R
S
S
H
H
G
G
P
P
D
D
A
A
K
K
610
|
L
L
L
L
A
A
G
G
G
G
E
E
D
D
V
V
A
A
P
P
620
|
G
G
P
P
L
L
G
G
L
L
G
G
Q
Q
L
L
L
L
A
A
630
|
V
V
A
A
S
S
Q
Q
V
V
A
A
A
A
G
G
M
M
V
V
640
|
Y
Y
L
L
A
A
G
G
L
L
H
H
F
F
V
V
H
H
R
R
650
|
D
D
L
L
A
A
T
T
R
R
N
N
C
C
L
L
V
V
G
G
660
|
Q
Q
G
G
L
L
V
V
V
V
K
K
I
I
G
G
D
D
F
F
670
|
G
G
M
M
S
S
R
R
D
D
I
I
Y
Y
S
S
T
T
D
D
680
|
Y
Y
Y
Y
R
R
V
V
G
G
G
G
R
R
T
T
M
M
L
L
690
|
P
P
I
I
R
R
W
W
M
M
P
P
P
P
E
E
S
S
I
I
700
|
L
L
Y
Y
R
R
K
K
F
F
T
T
T
T
E
E
S
S
D
D
710
|
V
V
W
W
S
S
F
F
G
G
V
V
V
V
L
L
W
W
E
E
720
|
I
I
F
F
T
T
Y
Y
G
G
K
K
Q
Q
P
P
W
W
Y
Y
730
|
Q
Q
L
L
S
S
N
N
T
T
E
E
A
A
I
I
D
D
C
C
740
|
I
I
T
T
Q
Q
G
G
R
R
E
E
L
L
E
E
R
R
P
P
750
|
R
R
A
A
C
C
P
P
P
P
E
E
V
V
Y
Y
A
A
I
I
760
|
M
M
R
R
G
G
C
C
W
W
Q
Q
R
R
E
E
P
P
Q
Q
770
|
Q
Q
R
R
H
H
S
S
I
I
K
K
D
D
V
V
H
H
A
A
780
|
R
R
L
L
Q
Q
A
A
L
L
A
A
Q
Q
A
A
P
P
P
P
790
|
V
V
Y
Y
L
L
D
D
V
V
L
L
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model KM-12 cells Colon Homo sapiens (Human) CVCL_1331
In Vivo Model NOD-SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 ddPCR; Kinase domain alignment assay
Larotrectinib
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: Tropomyosin-related kinase A (TrkA) [6]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Larotrectinib
 Drug Info 
Molecule Alteration Missense mutation
p.G595R (c.1783G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5H3Q
Mutant Type Structure Method: X-ray diffraction Resolution: 2.09  Å
PDB: 8J5X
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.93325
Amino acid change:
G595R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
S
-
L
-
S
-
P
-
T
-
480
|
E
-
G
-
K
-
G
-
S
-
G
-
L
-
Q
-
G
-
H
-
490
|
I
-
I
-
E
-
N
-
P
-
Q
-
Y
-
F
-
S
S
D
D
500
|
A
A
C
C
V
V
H
H
H
H
I
I
K
K
R
R
R
R
D
D
510
|
I
I
V
V
L
L
K
K
W
W
E
E
L
L
G
G
E
E
G
G
520
|
A
A
F
F
G
G
K
K
V
V
F
F
L
L
A
A
E
E
C
C
530
|
H
H
N
N
L
L
L
L
P
P
E
E
Q
Q
D
D
K
K
M
M
540
|
L
L
V
V
A
A
V
V
K
K
A
A
L
L
K
K
E
E
A
A
550
|
S
S
E
E
S
S
A
A
R
R
Q
Q
D
D
F
F
Q
Q
R
R
560
|
E
E
A
A
E
E
L
L
L
L
T
T
M
M
L
L
Q
Q
H
H
570
|
Q
Q
H
H
I
I
V
V
R
R
F
F
F
F
G
G
V
V
C
C
580
|
T
T
E
E
G
G
R
R
P
P
L
L
L
L
M
M
V
V
F
F
590
|
E
E
Y
Y
M
M
R
R
H
H
G
R
D
D
L
L
N
N
R
R
600
|
F
F
L
L
R
R
S
S
H
H
G
G
P
P
D
D
A
A
K
K
610
|
L
L
L
L
A
A
G
G
G
G
E
E
D
D
V
V
A
A
P
P
620
|
G
G
P
P
L
L
G
G
L
L
G
G
Q
Q
L
L
L
L
A
A
630
|
V
V
A
A
S
S
Q
Q
V
V
A
A
A
A
G
G
M
M
V
V
640
|
Y
Y
L
L
A
A
G
G
L
L
H
H
F
F
V
V
H
H
R
R
650
|
D
D
L
L
A
A
T
T
R
R
N
N
C
C
L
L
V
V
G
G
660
|
Q
Q
G
G
L
L
V
V
V
V
K
K
I
I
G
G
D
D
F
F
670
|
G
G
M
M
S
S
R
R
D
D
I
I
Y
Y
S
S
T
T
D
D
680
|
Y
Y
Y
Y
R
R
V
V
G
G
G
G
R
R
T
T
M
M
L
L
690
|
P
P
I
I
R
R
W
W
M
M
P
P
P
P
E
E
S
S
I
I
700
|
L
L
Y
Y
R
R
K
K
F
F
T
T
T
T
E
E
S
S
D
D
710
|
V
V
W
W
S
S
F
F
G
G
V
V
V
V
L
L
W
W
E
E
720
|
I
I
F
F
T
T
Y
Y
G
G
K
K
Q
Q
P
P
W
W
Y
Y
730
|
Q
Q
L
L
S
S
N
N
T
T
E
E
A
A
I
I
D
D
C
C
740
|
I
I
T
T
Q
Q
G
G
R
R
E
E
L
L
E
E
R
R
P
P
750
|
R
R
A
A
C
C
P
P
P
P
E
E
V
V
Y
Y
A
A
I
I
760
|
M
M
R
R
G
G
C
C
W
W
Q
Q
R
R
E
E
P
P
Q
Q
770
|
Q
Q
R
R
H
H
S
S
I
I
K
K
D
D
V
V
H
H
A
A
780
|
R
R
L
L
Q
Q
A
A
L
L
A
A
Q
Q
A
A
P
P
P
P
790
|
V
V
Y
Y
L
L
D
D
V
V
L
L
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
KM-12 cells Colon Homo sapiens (Human) CVCL_1331
In Vivo Model Balb-c nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Sanger sequencing assay; Western blot analysis
Experiment for
Drug Resistance		 CellTiter Glo assay; IC50 assay
Panitumumab
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 KRas (KRAS) [3]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Panitumumab
 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
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy assay
Mechanism Description Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.
Key Molecule: GTPase KRas (KRAS) [7], [2]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Panitumumab
 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
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: GTPase KRas (KRAS) [3]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.31  Å
PDB: 6T5V
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6MNX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.14
TM score: 0.96411
Amino acid change:
Q61H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
C
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
S
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
H
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
|
L
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
C
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
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		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy assay
Mechanism Description Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.
Key Molecule: GTPase KRas (KRAS) [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Missense mutation
p.G12R
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.50  Å
PDB: 6CU6
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.17
TM score: 0.95613
Amino acid change:
G12R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
R
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
C
C
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
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		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: GTPase KRas (KRAS) [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Missense mutation
p.G12A
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.45  Å
PDB: 8TBJ
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.06
TM score: 0.96454
Amino acid change:
G12A
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
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
A
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
C
C
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
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		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: GTPase KRas (KRAS) [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Missense mutation
p.G12C
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.60  Å
PDB: 8JGD
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.93157
Amino acid change:
G12C
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
C
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
C
C
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
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
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		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: GTPase KRas (KRAS) [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Missense mutation
p.G12S
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.24  Å
PDB: 4OBE
Mutant Type Structure Method: X-ray diffraction Resolution: 1.71  Å
PDB: 7TLK
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.85
TM score: 0.93473
Amino acid change:
G12S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
S
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
C
C
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
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		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: GTPase KRas (KRAS) [3]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 8JHL
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.9318
Amino acid change:
G12D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
D
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
C
C
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
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
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		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy assay
Mechanism Description Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.
Key Molecule: GTPase KRas (KRAS) [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 8JHL
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.9318
Amino acid change:
G12D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
D
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
C
C
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
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
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		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Missense mutation
p.V600E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Colon cells Colon Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy assay
Mechanism Description Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.
Regorafenib
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 KRas (KRAS) [8]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12V (c.35G>T)
 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 Revealed Based on the Cell Line Data
In Vitro Model KRAS cells N.A. N.A. N.A.
G12C cells N.A. N.A. N.A.
Experiment for
Molecule Alteration		 KRAS testing/KRAS quantification assay
Experiment for
Drug Resistance		 MTT assay
Key Molecule: GTPase KRas (KRAS) [8]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12R (c.34G>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.50  Å
PDB: 6CU6
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.17
TM score: 0.95613
Amino acid change:
G12R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
R
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
C
C
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
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model KRAS cells N.A. N.A. N.A.
G12C cells N.A. N.A. N.A.
Experiment for
Molecule Alteration		 KRAS testing/KRAS quantification assay
Experiment for
Drug Resistance		 MTT assay
Key Molecule: GTPase KRas (KRAS) [8]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12A (c.35G>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.45  Å
PDB: 8TBJ
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.06
TM score: 0.96454
Amino acid change:
G12A
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
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
A
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
C
C
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
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model KRAS cells N.A. N.A. N.A.
G12C cells N.A. N.A. N.A.
Experiment for
Molecule Alteration		 KRAS testing/KRAS quantification assay
Experiment for
Drug Resistance		 MTT assay
Key Molecule: GTPase KRas (KRAS) [8]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12C (c.34G>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.60  Å
PDB: 8JGD
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.93157
Amino acid change:
G12C
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
C
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
C
C
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
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model KRAS cells N.A. N.A. N.A.
G12C cells N.A. N.A. N.A.
Experiment for
Molecule Alteration		 KRAS testing/KRAS quantification assay
Experiment for
Drug Resistance		 MTT assay
Key Molecule: GTPase KRas (KRAS) [8]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12S (c.34G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.24  Å
PDB: 4OBE
Mutant Type Structure Method: X-ray diffraction Resolution: 1.71  Å
PDB: 7TLK
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.85
TM score: 0.93473
Amino acid change:
G12S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
S
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
C
C
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
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model KRAS cells N.A. N.A. N.A.
G12C cells N.A. N.A. N.A.
Experiment for
Molecule Alteration		 KRAS testing/KRAS quantification assay
Experiment for
Drug Resistance		 MTT assay
Key Molecule: GTPase KRas (KRAS) [8]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.G12D (c.35G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 8JHL
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.9318
Amino acid change:
G12D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
D
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
C
C
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
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model KRAS cells N.A. N.A. N.A.
G12C cells N.A. N.A. N.A.
Experiment for
Molecule Alteration		 KRAS testing/KRAS quantification assay
Experiment for
Drug Resistance		 MTT assay
Clinical Trial Drug(s)
5 drug(s) in total
Click to Show/Hide the Full List of Drugs
Enasidenib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [9]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Enasidenib
 Drug Info 
Molecule Alteration Missense mutation
p.R172K (c.515G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.93  Å
PDB: 5GIS
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5SVN
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.13
TM score: 0.29352
Amino acid change:
R172K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
A
-
D
-
K
-
R
-
I
-
K
-
V
-
A
-
K
-
P
50
|
-
V
-
V
-
E
-
M
-
D
-
G
-
D
-
E
-
M
-
T
60
|
-
R
-
I
-
I
-
W
-
Q
-
F
-
I
-
K
-
E
-
K
70
|
-
L
-
I
-
L
-
P
-
H
-
V
-
D
-
I
-
Q
-
L
80
|
-
K
-
Y
-
F
-
D
-
L
-
G
-
L
-
P
-
N
-
R
90
|
-
D
-
Q
-
T
-
D
-
D
-
Q
-
V
-
T
-
I
-
D
100
|
-
S
-
A
-
L
-
A
-
T
-
Q
-
K
-
Y
-
S
-
V
110
|
-
A
-
V
-
K
-
C
-
A
-
T
-
I
-
T
-
P
-
D
120
|
-
E
-
A
-
R
-
V
-
E
-
E
-
F
-
K
-
L
-
K
130
|
-
K
-
M
-
W
-
K
-
S
-
P
-
N
-
G
-
T
-
I
140
|
-
R
-
N
-
I
-
L
-
G
-
G
-
T
-
V
-
F
-
R
150
|
-
E
-
P
-
I
-
I
-
C
-
K
-
N
-
I
-
P
-
R
160
|
-
L
-
V
-
P
-
G
-
W
T
T
K
K
P
P
I
I
T
T
170
|
I
I
G
G
S
K
H
H
A
A
H
H
G
G
D
D
Q
Q
Y
Y
180
|
K
K
-
A
-
T
-
D
-
F
-
V
-
A
-
D
-
R
-
A
190
|
-
G
-
T
-
F
-
K
-
M
-
V
-
F
-
T
-
P
-
K
200
|
-
D
-
G
-
S
-
G
-
V
-
K
-
E
-
W
-
E
-
V
210
|
-
Y
-
N
-
F
-
P
-
A
-
G
-
G
-
V
-
G
-
M
220
|
-
G
-
M
-
Y
-
N
-
T
-
D
-
E
-
S
-
I
-
S
230
|
-
G
-
F
-
A
-
H
-
S
-
C
-
F
-
Q
-
Y
-
A
240
|
-
I
-
Q
-
K
-
K
-
W
-
P
-
L
-
Y
-
M
-
S
250
|
-
T
-
K
-
N
-
T
-
I
-
L
-
K
-
A
-
Y
-
D
260
|
-
G
-
R
-
F
-
K
-
D
-
I
-
F
-
Q
-
E
-
I
270
|
-
F
-
D
-
K
-
H
-
Y
-
K
-
T
-
D
-
F
-
D
280
|
-
K
-
N
-
K
-
I
-
W
-
Y
-
E
-
H
-
R
-
L
290
|
-
I
-
D
-
D
-
M
-
V
-
A
-
Q
-
V
-
L
-
K
300
|
-
S
-
S
-
G
-
G
-
F
-
V
-
W
-
A
-
C
-
K
310
|
-
N
-
Y
-
D
-
G
-
D
-
V
-
Q
-
S
-
D
-
I
320
|
-
L
-
A
-
Q
-
G
-
F
-
G
-
S
-
L
-
G
-
L
330
|
-
M
-
T
-
S
-
V
-
L
-
V
-
C
-
P
-
D
-
G
340
|
-
K
-
T
-
I
-
E
-
A
-
E
-
A
-
A
-
H
-
G
350
|
-
T
-
V
-
T
-
R
-
H
-
Y
-
R
-
E
-
H
-
Q
360
|
-
K
-
G
-
R
-
P
-
T
-
S
-
T
-
N
-
P
-
I
370
|
-
A
-
S
-
I
-
F
-
A
-
W
-
T
-
R
-
G
-
L
380
|
-
E
-
H
-
R
-
G
-
K
-
L
-
D
-
G
-
N
-
Q
390
|
-
D
-
L
-
I
-
R
-
F
-
A
-
Q
-
M
-
L
-
E
400
|
-
K
-
V
-
C
-
V
-
E
-
T
-
V
-
E
-
S
-
G
410
|
-
A
-
M
-
T
-
K
-
D
-
L
-
A
-
G
-
C
-
I
420
|
-
H
-
G
-
L
-
S
-
N
-
V
-
K
-
L
-
N
-
E
430
|
-
H
-
F
-
L
-
N
-
T
-
T
-
D
-
F
-
L
-
D
440
|
-
T
-
I
-
K
-
S
-
N
-
L
-
D
-
R
-
A
-
L
450
|
-
G
-
R
-
Q
-
S
-
L
-
E
-
H
-
H
-
H
-
H
460
|
-
H
-
H
-
H
-
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model U87MG cells Brain Homo sapiens (Human) CVCL_GP63
TF-1 cells Bone marrow Homo sapiens (Human) CVCL_0559
TF-1a cells Bone marrow Homo sapiens (Human) CVCL_3608
IDH2 cells Ovary Homo sapiens (Human) CVCL_D3DY
In Vivo Model NSG mouse PDX model Mus musculus
Mechanism Description Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.
Refametinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [10]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Refametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
A375 cells Skin Homo sapiens (Human) CVCL_0132
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
A431 cells Skin Homo sapiens (Human) CVCL_0037
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
BxPc3 cells Pancreas Homo sapiens (Human) CVCL_0186
SkMEL28 cells Skin Homo sapiens (Human) CVCL_0526
In Vivo Model Female athymic nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Biochemical kinase assays
Experiment for
Drug Resistance		 CellTiter 96 Aqueous One assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Refametinib by unusual activation of pro-survival pathway
Pimasertib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [11]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Pimasertib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
LOVO cells Colon Homo sapiens (Human) CVCL_0399
H1299 cells Lung Homo sapiens (Human) CVCL_0060
HCT15 cells Colon Homo sapiens (Human) CVCL_0292
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
In Vivo Model Female balb/c athymic (nu+/nu+) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Pimasertib by aberration of the drug's therapeutic target
Ulixertinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [12]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Ulixertinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
RkO cells Colon Homo sapiens (Human) CVCL_0504
G-361 cells Skin Homo sapiens (Human) CVCL_1220
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
SW48 cells Colon Homo sapiens (Human) CVCL_1724
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
AN3CA cells Ovary Homo sapiens (Human) CVCL_0028
MIA PaCa-2 cells Pancreas Homo sapiens (Human) CVCL_0428
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
In Vivo Model Athymic nude mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Standard coupled-enzyme assay
Lifirafenib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [13]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Lifirafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
SW620 cells Colon Homo sapiens (Human) CVCL_0547
HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
A431 cells Skin Homo sapiens (Human) CVCL_0037
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
WiDR cells Colon Homo sapiens (Human) CVCL_2760
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
SkMEL28 cells Skin Homo sapiens (Human) CVCL_0526
In Vivo Model Female NOD/SCID and BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay; Tumor volume measurement assay
Preclinical Drug(s)
25 drug(s) in total
Click to Show/Hide the Full List of Drugs
AGI-5198/Metformin
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: Oxalosuccinate decarboxylase (IDH1) [14]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug AGI-5198/Metformin
 Drug Info 
Molecule Alteration Missense mutation
p.R132H (c.395G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.65  Å
PDB: 6BKX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.88  Å
PDB: 4UMX
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.46
TM score: 0.85834
Amino acid change:
R132H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
S
S
K
K
K
K
I
I
S
S
G
G
G
G
S
S
10
|
V
V
V
V
E
E
M
M
Q
Q
G
G
D
D
E
E
M
M
T
T
20
|
R
R
I
I
I
I
W
W
E
E
L
L
I
I
K
K
E
E
K
K
30
|
L
L
I
I
F
F
P
P
Y
Y
V
V
E
E
L
L
D
D
L
L
40
|
H
H
S
S
Y
Y
D
D
L
L
G
G
I
I
E
E
N
N
R
R
50
|
D
D
A
A
T
T
N
N
D
D
Q
Q
V
V
T
T
K
K
D
D
60
|
A
A
A
A
E
E
A
A
I
I
K
K
K
K
H
H
N
N
V
V
70
|
G
G
V
V
K
K
C
C
A
A
T
T
I
I
T
T
P
P
D
D
80
|
E
E
K
K
R
R
V
V
E
E
E
E
F
F
K
K
L
L
K
K
90
|
Q
Q
M
M
W
W
K
K
S
S
P
P
N
N
G
G
T
T
I
I
100
|
R
R
N
N
I
I
L
L
G
G
G
G
T
T
V
V
F
F
R
R
110
|
E
E
A
A
I
I
I
I
C
C
K
K
N
N
I
I
P
P
R
R
120
|
L
L
V
V
S
S
G
G
W
W
V
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
R
H
H
H
A
A
Y
Y
G
G
D
D
Q
Q
Y
Y
140
|
R
R
A
A
T
T
D
D
F
F
V
V
V
V
P
P
G
G
P
P
150
|
G
G
K
K
V
V
E
E
I
I
T
T
Y
Y
T
T
P
P
S
S
160
|
D
D
G
G
T
T
Q
Q
K
K
V
V
T
T
Y
Y
L
L
V
V
170
|
H
H
N
N
F
F
E
E
E
E
G
G
G
G
G
G
V
V
A
A
180
|
M
M
G
G
M
M
Y
Y
N
N
Q
Q
D
D
K
K
S
S
I
I
190
|
E
E
D
D
F
F
A
A
H
H
S
S
S
S
F
F
Q
Q
M
M
200
|
A
A
L
L
S
S
K
K
G
G
W
W
P
P
L
L
Y
Y
L
L
210
|
S
S
T
T
K
K
N
N
T
T
I
I
L
L
K
K
K
K
Y
Y
220
|
D
D
G
G
R
R
F
F
K
K
D
D
I
I
F
F
Q
Q
E
E
230
|
I
I
Y
Y
D
D
K
K
Q
Q
Y
Y
K
K
S
S
Q
Q
F
F
240
|
E
E
A
A
Q
Q
K
K
I
I
W
W
Y
Y
E
E
H
H
R
R
250
|
L
L
I
I
D
D
D
D
M
M
V
V
A
A
Q
Q
A
A
M
M
260
|
K
K
S
S
E
E
G
G
G
G
F
F
I
I
W
W
A
A
C
C
270
|
K
K
N
N
Y
Y
D
D
G
G
D
D
V
V
Q
Q
S
S
D
D
280
|
S
S
V
V
A
A
Q
Q
G
G
Y
Y
G
G
S
S
L
L
G
G
290
|
M
M
M
M
T
T
S
S
V
V
L
L
V
V
C
C
P
P
D
D
300
|
G
G
K
K
T
T
V
V
E
E
A
A
E
E
A
A
A
A
H
H
310
|
G
G
T
T
V
V
T
T
R
R
H
H
Y
Y
R
R
M
M
Y
Y
320
|
Q
Q
K
K
G
G
Q
Q
E
E
T
T
S
S
T
T
N
N
P
P
330
|
I
I
A
A
S
S
I
I
F
F
A
A
W
W
T
T
R
R
G
G
340
|
L
L
A
A
H
H
R
R
A
A
K
K
L
L
D
D
N
N
N
N
350
|
K
K
E
E
L
L
A
A
F
F
F
F
A
A
N
N
A
A
L
L
360
|
E
E
E
E
V
V
S
S
I
I
E
E
T
T
I
I
E
E
A
A
370
|
G
G
F
F
M
M
T
T
K
K
D
D
L
L
A
A
A
A
C
C
380
|
I
I
K
K
G
G
L
L
P
P
N
N
V
V
Q
Q
R
R
S
S
390
|
D
D
Y
Y
L
L
N
N
T
T
F
F
E
E
F
F
M
M
D
D
400
|
K
K
L
L
G
G
E
E
N
N
L
L
K
K
I
I
K
K
L
L
410
|
A
A
Q
Q
A
A
K
K
L
L
S
S
L
L
E
E
H
H
H
H
420
|
H
H
H
H
H
H
H
H
H
H
H
H
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
IDH1 cells Ovary Homo sapiens (Human) CVCL_D3DY
Experiment for
Molecule Alteration		 Western blot analysis; gama-H2AX immunofluorescence staining and measurement
Experiment for
Drug Resistance		 Colony formation assay
Alpelisib/Cetuximab/Encorafenib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [15]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Alpelisib/Cetuximab/Encorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vitro Model WiDR cells Colon Homo sapiens (Human) CVCL_2760
VACO432 cells Colon Homo sapiens (Human) CVCL_5402
HROC87 cells Colon Homo sapiens (Human) CVCL_S854
Experiment for
Molecule Alteration		 SDS-PAGE assay; Western blot analysis; chemiluminescent detection assay
Experiment for
Drug Resistance		 CellTiter-Glo luminescent assay; CellTox green assay
Mechanism Description Resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway.
BAY1217389
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Catenin beta-1 (CTNNB1) [16]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug BAY1217389
 Drug Info 
Molecule Alteration Missense mutation
p.S45F (c.134C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6O9B
Mutant Type Structure Method: X-ray diffraction Resolution: 2.45  Å
PDB: 6O9C
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.23
TM score: 0.84883
Amino acid change:
S45F
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
T
T
T
T
A
A
P
P
S
F
L
L
S
S
G
G
K
K
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
SW48 cells Colon Homo sapiens (Human) CVCL_1724
TOV-21G cells Ovary Homo sapiens (Human) CVCL_3613
HuTu80 cells Small intestine Homo sapiens (Human) CVCL_1301
TOV-112D cells Ovary Homo sapiens (Human) CVCL_3612
LS 174T cells Colon Homo sapiens (Human) CVCL_1384
A427 cells Lung Homo sapiens (Human) CVCL_1055
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Gene set analysis
Experiment for
Drug Resistance		 Cell proliferation assay
Mechanism Description The missense mutation p.S45F (c.134C>T) in gene CTNNB1 cause the sensitivity of BAY1217389 by unusual activation of pro-survival pathway
CCT196969
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [17]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug CCT196969
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
CCT241161
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [17]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug CCT241161
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
In Vivo Model Female nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Cetuximab/Selumetinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [15]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Cetuximab/Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vitro Model WiDR cells Colon Homo sapiens (Human) CVCL_2760
VACO432 cells Colon Homo sapiens (Human) CVCL_5402
HROC87 cells Colon Homo sapiens (Human) CVCL_S854
Experiment for
Molecule Alteration		 SDS-PAGE assay; Western blot analysis; chemiluminescent detection assay
Experiment for
Drug Resistance		 CellTiter-Glo luminescent assay; CellTox green assay
Mechanism Description Resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway.
Cetuximab/Trametinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 1 (MEK1) [18]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Cetuximab/Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.C121S (c.361T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7B7R
Mutant Type Structure Method: X-ray diffraction Resolution: 2.01  Å
PDB: 7F2X
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.36
TM score: 0.87257
Amino acid change:
C121S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
20
|
M
-
A
-
H
-
H
-
H
-
H
-
H
-
H
-
A
-
A
-
30
|
A
-
E
-
N
-
L
-
Y
-
F
-
Q
-
L
-
E
-
E
-
40
|
L
-
E
-
L
M
D
T
E
L
Q
Q
Q
Q
R
R
K
K
R
R
50
|
L
L
E
E
A
A
F
F
L
L
T
T
Q
Q
K
K
Q
Q
K
K
60
|
V
V
G
G
E
E
L
L
K
K
D
D
D
D
D
D
F
F
E
E
70
|
K
K
I
I
S
S
E
E
L
L
G
G
A
A
G
G
N
N
G
G
80
|
G
G
V
V
V
V
F
F
K
K
V
V
S
S
H
H
K
K
P
P
90
|
S
S
G
G
L
L
V
V
M
M
A
A
R
R
K
K
L
L
I
I
100
|
H
H
L
L
E
E
I
I
K
K
P
P
A
A
I
I
R
R
N
N
110
|
Q
Q
I
I
I
I
R
R
E
E
L
L
Q
Q
V
V
L
L
H
H
120
|
E
E
C
S
N
N
S
S
P
P
Y
Y
I
I
V
V
G
G
F
F
130
|
Y
Y
G
G
A
A
F
F
Y
Y
S
S
D
D
G
G
E
E
I
I
140
|
S
S
I
I
C
C
M
M
E
E
H
H
M
M
D
D
G
G
G
G
150
|
S
S
L
L
D
D
Q
Q
V
V
L
L
K
K
K
K
A
A
G
G
160
|
R
R
I
I
P
P
E
E
Q
Q
I
I
L
L
G
G
K
K
V
V
170
|
S
S
I
I
A
A
V
V
I
I
K
K
G
G
L
L
T
T
Y
Y
180
|
L
L
R
R
E
E
K
K
H
H
K
K
I
I
M
M
H
H
R
R
190
|
D
D
V
V
K
K
P
P
S
S
N
N
I
I
L
L
V
V
N
N
200
|
S
S
R
R
G
G
E
E
I
I
K
K
L
L
C
C
D
D
F
F
210
|
G
G
V
V
S
S
G
G
Q
Q
L
L
I
I
D
D
S
S
M
M
220
|
A
A
N
N
S
S
F
F
V
V
G
G
T
T
R
R
S
S
Y
Y
230
|
M
M
S
S
P
P
E
E
R
R
L
L
Q
Q
G
G
T
T
H
H
240
|
Y
Y
S
S
V
V
Q
Q
S
S
D
D
I
I
W
W
S
S
M
M
250
|
G
G
L
L
S
S
L
L
V
V
E
E
M
M
A
A
V
V
G
G
260
|
R
R
Y
Y
P
P
I
I
-
G
-
S
-
G
-
S
-
G
-
S
270
|
-
M
-
A
-
I
-
F
-
E
-
L
-
L
-
D
-
Y
-
I
280
|
-
V
-
N
-
E
-
P
-
P
-
P
-
K
-
L
-
P
-
S
290
|
-
G
-
V
-
F
-
S
-
L
-
E
-
F
-
Q
-
D
-
F
300
|
-
V
-
N
G
K
S
C
G
L
S
I
G
K
S
N
M
P
A
A
310
|
I
E
F
R
E
A
L
D
L
L
D
K
Y
Q
I
L
V
M
N
V
320
|
E
H
P
A
P
F
P
I
K
K
L
R
P
S
S
D
G
A
V
E
330
|
F
E
S
V
L
D
E
F
F
A
Q
G
D
W
F
L
V
C
N
S
340
|
K
T
C
I
L
G
I
L
K
N
N
Q
P
P
A
S
E
T
R
P
350
|
A
T
D
H
L
A
K
A
Q
G
L
E
M
G
V
H
H
H
A
H
360
|
F
H
I
H
K
H
R
-
S
-
D
-
A
-
E
-
E
-
V
-
370
|
D
-
F
-
A
-
G
-
W
-
L
-
C
-
S
-
T
-
I
-
380
|
G
-
L
-
N
-
Q
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
CCK-81 cells N.A. Homo sapiens (Human) CVCL_2873
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [18]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Cetuximab/Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.G12V (c.35G>T)
 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 Revealed Based on the Cell Line Data
In Vitro Model NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
CCK-81 cells N.A. Homo sapiens (Human) CVCL_2873
Dactolisib/Selumetinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase KRas (KRAS) [19]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Dactolisib/Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.A146T (c.436G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7VVB
Mutant Type Structure Method: X-ray diffraction Resolution: 1.18  Å
PDB: 8EDY
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.54
TM score: 0.82894
Amino acid change:
A146T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
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
C
C
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
T
K
K
T
T
R
R
150
|
Q
Q
R
G
V
V
E
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
K
Y
H
R
K
L
E
K
K
170
|
K
M
I
S
S
K
K
D
E
G
E
K
K
K
T
K
P
K
G
K
180
|
C
K
V
S
K
K
I
T
K
K
K
S
C
-
I
-
I
-
M
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Liver N.A.
In Vivo Model Female nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunohistochemistry assay
Mechanism Description The missense mutation p.A146T (c.436G>A) in gene KRAS cause the sensitivity of Dactolisib + Selumetinib by unusual activation of pro-survival pathway
Key Molecule: GTPase KRas (KRAS) [19]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Dactolisib/Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.G13D (c.38G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.01  Å
PDB: 6P0Z
Mutant Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 8BLR
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.48
TM score: 0.8385
Amino acid change:
G13D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
-
G
-
G
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
D
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
C
C
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
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Liver N.A.
In Vivo Model Female nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunohistochemistry assay
Mechanism Description The missense mutation p.G13D (c.38G>A) in gene KRAS cause the sensitivity of Dactolisib + Selumetinib by unusual activation of pro-survival pathway
DEL-22379
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [20]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug DEL-22379
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
In Vivo Model Female athymic nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Caspase-Glo 3/7 luminogenic assay
INU-152
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [21]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug INU-152
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
In Vitro Model HT-29 cells Colon Homo sapiens (Human) CVCL_0320
A375 cells Skin Homo sapiens (Human) CVCL_0132
HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
SkMEL2 cells Skin Homo sapiens (Human) CVCL_0069
Colo-205 cells Ascites Homo sapiens (Human) CVCL_0218
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description INU-152 inhibits all RAF isoforms and inhibits MAPK pathways in mutant BRAF cells. More importantly, INU-152 exhibits minimal paradoxical pathway activation in melanoma cells with mutant RAS. INU-152 exhibits anti-tumor activities in xenograft models carrying BRAF mutations.
LSN3074753
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [22]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug LSN3074753
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
EGFR signaling pathway Inhibition hsa01521
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
MM-151
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [23]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug MM-151
 Drug Info 
Molecule Alteration Missense mutation
p.S492R (c.1476C>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 3C09
Mutant Type Structure Method: X-ray diffraction Resolution: 2.80  Å
PDB: 6B3S
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.58
TM score: 0.98774
Amino acid change:
S492R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
L
L
E
E
E
E
310
|
K
K
K
K
V
V
C
C
N
N
G
G
I
I
G
G
I
I
G
G
320
|
E
E
F
F
K
K
D
D
S
S
L
L
S
S
I
I
N
N
A
A
330
|
T
T
N
N
I
I
K
K
H
H
F
F
K
K
N
N
C
C
T
T
340
|
S
S
I
I
S
S
G
G
D
D
L
L
H
H
I
I
L
L
P
P
350
|
V
V
A
A
F
F
R
R
G
G
D
D
S
S
F
F
T
T
H
H
360
|
T
T
P
P
P
P
L
L
D
D
P
P
Q
Q
E
E
L
L
D
D
370
|
I
I
L
L
K
K
T
T
V
V
K
K
E
E
I
I
T
T
G
G
380
|
F
F
L
L
L
L
I
I
Q
Q
A
A
W
W
P
P
E
E
N
N
390
|
R
R
T
T
D
D
L
L
H
H
A
A
F
F
E
E
N
N
L
L
400
|
E
E
I
I
I
I
R
R
G
G
R
R
T
T
K
K
Q
Q
H
H
410
|
G
G
Q
Q
F
F
S
S
L
L
A
A
V
V
V
V
S
S
L
L
420
|
N
N
I
I
T
T
S
S
L
L
G
G
L
L
R
R
S
S
L
L
430
|
K
K
E
E
I
I
S
S
D
D
G
G
D
D
V
V
I
I
I
I
440
|
S
S
G
G
N
N
K
K
N
N
L
L
C
C
Y
Y
A
A
N
N
450
|
T
T
I
I
N
N
W
W
K
K
K
K
L
L
F
F
G
G
T
T
460
|
S
S
G
G
Q
Q
K
K
T
T
K
K
I
I
I
I
S
R
N
N
470
|
R
R
G
G
E
E
N
N
S
S
C
C
K
K
A
A
T
T
G
G
480
|
Q
Q
V
V
C
C
H
H
A
A
L
L
C
C
S
S
P
P
E
E
490
|
G
G
C
C
W
W
G
G
P
P
E
E
P
P
R
R
D
D
C
C
500
|
V
V
S
S
C
C
R
R
N
N
V
V
S
S
R
R
G
G
R
R
510
|
E
E
C
C
V
V
D
D
K
K
H
H
H
H
H
H
H
H
H
H
520
|
H
H
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation AKT/ERK signaling pathway Inhibition hsa04010
In Vitro Model LIM1215 cells Colon Homo sapiens (Human) CVCL_2574
HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade.
MPI-0479605
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Catenin beta-1 (CTNNB1) [16]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug MPI-0479605
 Drug Info 
Molecule Alteration Missense mutation
p.S45F (c.134C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6O9B
Mutant Type Structure Method: X-ray diffraction Resolution: 2.45  Å
PDB: 6O9C
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.23
TM score: 0.84883
Amino acid change:
S45F
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
T
T
T
T
A
A
P
P
S
F
L
L
S
S
G
G
K
K
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
SW48 cells Colon Homo sapiens (Human) CVCL_1724
TOV-21G cells Ovary Homo sapiens (Human) CVCL_3613
HuTu80 cells Small intestine Homo sapiens (Human) CVCL_1301
TOV-112D cells Ovary Homo sapiens (Human) CVCL_3612
LS 174T cells Colon Homo sapiens (Human) CVCL_1384
A427 cells Lung Homo sapiens (Human) CVCL_1055
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Gene set analysis
Experiment for
Drug Resistance		 Cell proliferation assay
Mechanism Description The missense mutation p.S45F (c.134C>T) in gene CTNNB1 cause the sensitivity of MPI-0479605 by unusual activation of pro-survival pathway
Mps-BAY2b
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Catenin beta-1 (CTNNB1) [16]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Mps-BAY2b
 Drug Info 
Molecule Alteration Missense mutation
p.S45F (c.134C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6O9B
Mutant Type Structure Method: X-ray diffraction Resolution: 2.45  Å
PDB: 6O9C
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.23
TM score: 0.84883
Amino acid change:
S45F
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
T
T
T
T
A
A
P
P
S
F
L
L
S
S
G
G
K
K
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
SW48 cells Colon Homo sapiens (Human) CVCL_1724
TOV-21G cells Ovary Homo sapiens (Human) CVCL_3613
HuTu80 cells Small intestine Homo sapiens (Human) CVCL_1301
TOV-112D cells Ovary Homo sapiens (Human) CVCL_3612
LS 174T cells Colon Homo sapiens (Human) CVCL_1384
A427 cells Lung Homo sapiens (Human) CVCL_1055
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Gene set analysis
Experiment for
Drug Resistance		 Cell proliferation assay
Mechanism Description The missense mutation p.S45F (c.134C>T) in gene CTNNB1 cause the sensitivity of Mps-BAY2b by unusual activation of pro-survival pathway
Mps1-IN-1
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Catenin beta-1 (CTNNB1) [16]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Mps1-IN-1
 Drug Info 
Molecule Alteration Missense mutation
p.S45F (c.134C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6O9B
Mutant Type Structure Method: X-ray diffraction Resolution: 2.45  Å
PDB: 6O9C
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.23
TM score: 0.84883
Amino acid change:
S45F
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
T
T
T
T
A
A
P
P
S
F
L
L
S
S
G
G
K
K
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
SW48 cells Colon Homo sapiens (Human) CVCL_1724
TOV-21G cells Ovary Homo sapiens (Human) CVCL_3613
HuTu80 cells Small intestine Homo sapiens (Human) CVCL_1301
TOV-112D cells Ovary Homo sapiens (Human) CVCL_3612
LS 174T cells Colon Homo sapiens (Human) CVCL_1384
A427 cells Lung Homo sapiens (Human) CVCL_1055
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Gene set analysis
Experiment for
Drug Resistance		 Cell proliferation assay
Mechanism Description The missense mutation p.S45F (c.134C>T) in gene CTNNB1 cause the sensitivity of Mps1-IN-1 by unusual activation of pro-survival pathway
NSC59984
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cellular tumor antigen p53 (TP53) [24]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug NSC59984
 Drug Info 
Molecule Alteration Missense mutation
p.R175H (c.524G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.37  Å
PDB: 6VR1
Mutant Type Structure Method: X-ray diffraction Resolution: 2.38  Å
PDB: 6VR5
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.18
TM score: 0.89418
Amino acid change:
R175H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
H
H
M
M
170
|
T
T
E
E
V
V
V
V
R
R
R
H
C
C
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model SW480 cells Colon Homo sapiens (Human) CVCL_0546
HCT116 cells Colon Homo sapiens (Human) CVCL_0291
DLD-1 cells Colon Homo sapiens (Human) CVCL_0248
RXF393 cells Kidney Homo sapiens (Human) CVCL_1673
MRC5 cells Fetal lung Homo sapiens (Human) CVCL_0440
Wi38 cells Fetal lung Homo sapiens (Human) CVCL_0579
Hop92 cells Lung Homo sapiens (Human) CVCL_1286
In Vivo Model Female CRL nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Semi-quantitative RT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay; Colony formation assay
NTRC 0066-0
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Catenin beta-1 (CTNNB1) [16]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug NTRC 0066-0
 Drug Info 
Molecule Alteration Missense mutation
p.S45F (c.134C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6O9B
Mutant Type Structure Method: X-ray diffraction Resolution: 2.45  Å
PDB: 6O9C
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.23
TM score: 0.84883
Amino acid change:
S45F
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
T
T
T
T
A
A
P
P
S
F
L
L
S
S
G
G
K
K
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
SW48 cells Colon Homo sapiens (Human) CVCL_1724
TOV-21G cells Ovary Homo sapiens (Human) CVCL_3613
HuTu80 cells Small intestine Homo sapiens (Human) CVCL_1301
TOV-112D cells Ovary Homo sapiens (Human) CVCL_3612
LS 174T cells Colon Homo sapiens (Human) CVCL_1384
A427 cells Lung Homo sapiens (Human) CVCL_1055
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Gene set analysis
Experiment for
Drug Resistance		 Cell proliferation assay
Mechanism Description The missense mutation p.S45F (c.134C>T) in gene CTNNB1 cause the sensitivity of NTRC 0066-0 by unusual activation of pro-survival pathway
Pan-TRK inhibitors
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: Tropomyosin-related kinase A (TrkA) [5]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug Pan-TRK inhibitors
 Drug Info 
Molecule Alteration Missense mutation
p.G595R (c.1783G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5H3Q
Mutant Type Structure Method: X-ray diffraction Resolution: 2.09  Å
PDB: 8J5X
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.93325
Amino acid change:
G595R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
S
-
L
-
S
-
P
-
T
-
480
|
E
-
G
-
K
-
G
-
S
-
G
-
L
-
Q
-
G
-
H
-
490
|
I
-
I
-
E
-
N
-
P
-
Q
-
Y
-
F
-
S
S
D
D
500
|
A
A
C
C
V
V
H
H
H
H
I
I
K
K
R
R
R
R
D
D
510
|
I
I
V
V
L
L
K
K
W
W
E
E
L
L
G
G
E
E
G
G
520
|
A
A
F
F
G
G
K
K
V
V
F
F
L
L
A
A
E
E
C
C
530
|
H
H
N
N
L
L
L
L
P
P
E
E
Q
Q
D
D
K
K
M
M
540
|
L
L
V
V
A
A
V
V
K
K
A
A
L
L
K
K
E
E
A
A
550
|
S
S
E
E
S
S
A
A
R
R
Q
Q
D
D
F
F
Q
Q
R
R
560
|
E
E
A
A
E
E
L
L
L
L
T
T
M
M
L
L
Q
Q
H
H
570
|
Q
Q
H
H
I
I
V
V
R
R
F
F
F
F
G
G
V
V
C
C
580
|
T
T
E
E
G
G
R
R
P
P
L
L
L
L
M
M
V
V
F
F
590
|
E
E
Y
Y
M
M
R
R
H
H
G
R
D
D
L
L
N
N
R
R
600
|
F
F
L
L
R
R
S
S
H
H
G
G
P
P
D
D
A
A
K
K
610
|
L
L
L
L
A
A
G
G
G
G
E
E
D
D
V
V
A
A
P
P
620
|
G
G
P
P
L
L
G
G
L
L
G
G
Q
Q
L
L
L
L
A
A
630
|
V
V
A
A
S
S
Q
Q
V
V
A
A
A
A
G
G
M
M
V
V
640
|
Y
Y
L
L
A
A
G
G
L
L
H
H
F
F
V
V
H
H
R
R
650
|
D
D
L
L
A
A
T
T
R
R
N
N
C
C
L
L
V
V
G
G
660
|
Q
Q
G
G
L
L
V
V
V
V
K
K
I
I
G
G
D
D
F
F
670
|
G
G
M
M
S
S
R
R
D
D
I
I
Y
Y
S
S
T
T
D
D
680
|
Y
Y
Y
Y
R
R
V
V
G
G
G
G
R
R
T
T
M
M
L
L
690
|
P
P
I
I
R
R
W
W
M
M
P
P
P
P
E
E
S
S
I
I
700
|
L
L
Y
Y
R
R
K
K
F
F
T
T
T
T
E
E
S
S
D
D
710
|
V
V
W
W
S
S
F
F
G
G
V
V
V
V
L
L
W
W
E
E
720
|
I
I
F
F
T
T
Y
Y
G
G
K
K
Q
Q
P
P
W
W
Y
Y
730
|
Q
Q
L
L
S
S
N
N
T
T
E
E
A
A
I
I
D
D
C
C
740
|
I
I
T
T
Q
Q
G
G
R
R
E
E
L
L
E
E
R
R
P
P
750
|
R
R
A
A
C
C
P
P
P
P
E
E
V
V
Y
Y
A
A
I
I
760
|
M
M
R
R
G
G
C
C
W
W
Q
Q
R
R
E
E
P
P
Q
Q
770
|
Q
Q
R
R
H
H
S
S
I
I
K
K
D
D
V
V
H
H
A
A
780
|
R
R
L
L
Q
Q
A
A
L
L
A
A
Q
Q
A
A
P
P
P
P
790
|
V
V
Y
Y
L
L
D
D
V
V
L
L
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model KM-12 cells Colon Homo sapiens (Human) CVCL_1331
In Vivo Model NOD-SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 ddPCR; Kinase domain alignment assay
Pimasertib/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: Serine/threonine-protein kinase B-raf (BRAF) [11]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Pimasertib/Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
LOVO cells Colon Homo sapiens (Human) CVCL_0399
H1299 cells Lung Homo sapiens (Human) CVCL_0060
HCT15 cells Colon Homo sapiens (Human) CVCL_0292
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
In Vivo Model Female balb/c athymic (nu+/nu+) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Pimasertib + Regorafenib by aberration of the drug's therapeutic target
PLX4720/Pictilisib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [25]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug PLX4720/Pictilisib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Experiment for
Molecule Alteration		 DNA sequencing assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 + Pictilisib by aberration of the drug's therapeutic target
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [25]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug PLX4720/Pictilisib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Experiment for
Molecule Alteration		 DNA sequencing assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 + Pictilisib by aberration of the drug's therapeutic target
PLX7904
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [26]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug PLX7904
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
A431 cells Skin Homo sapiens (Human) CVCL_0037
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
SkMEL239-C3 cells Skin Homo sapiens (Human) CVCL_6122
SkMEL239 cells Skin Homo sapiens (Human) CVCL_6122
IPC-298 cells Skin Homo sapiens (Human) CVCL_1307
Colo829 cells Skin Homo sapiens (Human) CVCL_1137
B9 cells N.A. Mus musculus (Mouse) CVCL_1952
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Microarray gene expression analysis; Crystallization and structure determination assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; Anchorage-independent growth assay
Selumetinib/Dactolisib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase KRas (KRAS) [19]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Selumetinib/Dactolisib
 Drug Info 
Molecule Alteration Missense mutation
p.G12V (c.35G>T)
 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
In Vitro Model Liver N.A.
In Vivo Model Female nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunohistochemistry assay
Mechanism Description The missense mutation p.G12V (c.35G>T) in gene KRAS cause the sensitivity of Selumetinib + Dactolisib by unusual activation of pro-survival pathway
Key Molecule: GTPase KRas (KRAS) [19]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Selumetinib/Dactolisib
 Drug Info 
Molecule Alteration Missense mutation
p.A146V (c.437C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7VVB
Mutant Type Structure Method: X-ray diffraction Resolution: 1.18  Å
PDB: 8EER
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.5
TM score: 0.82604
Amino acid change:
A146V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
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
C
C
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
V
K
K
T
T
R
R
150
|
Q
Q
R
G
V
V
E
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
K
Y
H
R
K
L
E
K
K
170
|
K
M
I
S
S
K
K
D
E
G
E
K
K
K
T
K
P
K
G
K
180
|
C
K
V
S
K
K
I
T
K
K
K
S
C
-
I
-
I
-
M
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Liver N.A.
In Vivo Model Female nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunohistochemistry assay
Mechanism Description The missense mutation p.A146V (c.437C>T) in gene KRAS cause the sensitivity of Selumetinib + Dactolisib by unusual activation of pro-survival pathway
Key Molecule: GTPase Nras (NRAS) [19]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Selumetinib/Dactolisib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61K (c.181C>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
|
-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
-
F
-
Q
0
|
S
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Liver N.A.
In Vivo Model Female nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunohistochemistry assay
Mechanism Description The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Selumetinib + Dactolisib by unusual activation of pro-survival pathway
Key Molecule: GTPase KRas (KRAS) [19]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Selumetinib/Dactolisib
 Drug Info 
Molecule Alteration Missense mutation
p.G12C (c.34G>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.60  Å
PDB: 8JGD
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.93157
Amino acid change:
G12C
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
C
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
C
C
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
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Liver N.A.
In Vivo Model Female nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunohistochemistry assay
Mechanism Description The missense mutation p.G12C (c.34G>T) in gene KRAS cause the sensitivity of Selumetinib + Dactolisib by unusual activation of pro-survival pathway
Key Molecule: GTPase KRas (KRAS) [19]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Selumetinib/Dactolisib
 Drug Info 
Molecule Alteration Missense mutation
p.G12D (c.35G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 8JHL
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.9318
Amino acid change:
G12D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
D
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
C
C
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
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Liver N.A.
In Vivo Model Female nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Immunohistochemistry assay
Mechanism Description The missense mutation p.G12D (c.35G>A) in gene KRAS cause the sensitivity of Selumetinib + Dactolisib by unusual activation of pro-survival pathway
SHP099
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [27]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug SHP099
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation RAS/ERK signaling pathway Inhibition hsa01521
In Vitro Model MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
NCI-H2228 cells Lung Homo sapiens (Human) CVCL_1543
MDA-MB-468 cells Breast Homo sapiens (Human) CVCL_0419
A2058 cells Skin Homo sapiens (Human) CVCL_1059
KYSE520 cells Esophagus Homo sapiens (Human) CVCL_1355
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
Sum52 cells Pleural effusion Homo sapiens (Human) CVCL_3425
NCI-H2170 cells Lung Homo sapiens (Human) CVCL_1535
NCI-H2170 cells Lung Homo sapiens (Human) CVCL_1535
H293 cells Kidney Homo sapiens (Human) N.A.
In Vivo Model Athymic nude mouse PDX model Mus musculus
Experiment for
Drug Resistance		 CellTitre-Glo assay; Crystal violet staining assay
Mechanism Description SHP099 suppresses RAS-ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models.
TAK-632
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [28]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug TAK-632
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model SW1736 cells Thyroid Homo sapiens (Human) CVCL_3883
8505C cells Thyroid Homo sapiens (Human) CVCL_1054
Hth104 cells Thyroid gland Homo sapiens (Human) CVCL_A427
In Vivo Model Mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of TAK-632 by aberration of the drug's therapeutic target
Vemurafenib/Capecitabine/Bevacizumab
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [29]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Vemurafenib/Capecitabine/Bevacizumab
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Colo741 cells Pelvis Homo sapiens (Human) CVCL_1133
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Vemurafenib + Capecitabine + Bevacizumab by aberration of the drug's therapeutic target
Investigative Drug(s)
8 drug(s) in total
Click to Show/Hide the Full List of Drugs
Binimetinib/Cetuximab/Encorafenib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [30]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Binimetinib/Cetuximab/Encorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cobimetinib/Vemurafenib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [31]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Cobimetinib/Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
EGFR inhibitors
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 Hras (HRAS) [32]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug EGFR inhibitors
 Drug Info 
Molecule Alteration Missense mutation
p.G13D (c.38G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.01  Å
PDB: 6P0Z
Mutant Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 8BLR
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.48
TM score: 0.8385
Amino acid change:
G13D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
-
G
-
G
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
D
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
C
C
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
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Colorectum N.A.
Folfox protocol
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Glutathione S-transferase P (GSTP1) [33]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Folfox protocol
 Drug Info 
Molecule Alteration Missense mutation
p.I105V (c.313A>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 2A2R
Mutant Type Structure Method: X-ray diffraction Resolution: 1.80  Å
PDB: 1PGT
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.32
TM score: 0.99645
Amino acid change:
I105V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
P
P
P
P
Y
Y
T
T
V
V
V
V
Y
Y
F
F
10
|
P
P
V
V
R
R
G
G
R
R
C
C
A
A
A
A
L
L
R
R
20
|
M
M
L
L
L
L
A
A
D
D
Q
Q
G
G
Q
Q
S
S
W
W
30
|
K
K
E
E
E
E
V
V
V
V
T
T
V
V
E
E
T
T
W
W
40
|
Q
Q
E
E
G
G
S
S
L
L
K
K
A
A
S
S
C
C
L
L
50
|
Y
Y
G
G
Q
Q
L
L
P
P
K
K
F
F
Q
Q
D
D
G
G
60
|
D
D
L
L
T
T
L
L
Y
Y
Q
Q
S
S
N
N
T
T
I
I
70
|
L
L
R
R
H
H
L
L
G
G
R
R
T
T
L
L
G
G
L
L
80
|
Y
Y
G
G
K
K
D
D
Q
Q
Q
Q
E
E
A
A
A
A
L
L
90
|
V
V
D
D
M
M
V
V
N
N
D
D
G
G
V
V
E
E
D
D
100
|
L
L
R
R
C
C
K
K
Y
Y
I
V
S
S
L
L
I
I
Y
Y
110
|
T
T
N
N
Y
Y
E
E
A
A
G
G
K
K
D
D
D
D
Y
Y
120
|
V
V
K
K
A
A
L
L
P
P
G
G
Q
Q
L
L
K
K
P
P
130
|
F
F
E
E
T
T
L
L
L
L
S
S
Q
Q
N
N
Q
Q
G
G
140
|
G
G
K
K
T
T
F
F
I
I
V
V
G
G
D
D
Q
Q
I
I
150
|
S
S
F
F
A
A
D
D
Y
Y
N
N
L
L
L
L
D
D
L
L
160
|
L
L
L
L
I
I
H
H
E
E
V
V
L
L
A
A
P
P
G
G
170
|
C
C
L
L
D
D
A
A
F
F
P
P
L
L
L
L
S
S
A
A
180
|
Y
Y
V
V
G
G
R
R
L
L
S
S
A
A
R
R
P
P
K
K
190
|
L
L
K
K
A
A
F
F
L
L
A
A
S
S
P
P
E
E
Y
Y
200
|
V
V
N
N
L
L
P
P
I
I
N
N
G
G
N
N
G
G
K
K
210
|
Q
Q
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Human colorectal carcinoma tissue N.A.
Mechanism Description The missense mutation p.I105V (c.313A>G) in gene GSTP1 cause the sensitivity of Folfox Protocol by drug inactivation by structure modification
Futuximab
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [34]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Futuximab
 Drug Info 
Molecule Alteration Missense mutation
p.S492R (c.1476C>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 3C09
Mutant Type Structure Method: X-ray diffraction Resolution: 2.80  Å
PDB: 6B3S
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.58
TM score: 0.98774
Amino acid change:
S492R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
L
L
E
E
E
E
310
|
K
K
K
K
V
V
C
C
N
N
G
G
I
I
G
G
I
I
G
G
320
|
E
E
F
F
K
K
D
D
S
S
L
L
S
S
I
I
N
N
A
A
330
|
T
T
N
N
I
I
K
K
H
H
F
F
K
K
N
N
C
C
T
T
340
|
S
S
I
I
S
S
G
G
D
D
L
L
H
H
I
I
L
L
P
P
350
|
V
V
A
A
F
F
R
R
G
G
D
D
S
S
F
F
T
T
H
H
360
|
T
T
P
P
P
P
L
L
D
D
P
P
Q
Q
E
E
L
L
D
D
370
|
I
I
L
L
K
K
T
T
V
V
K
K
E
E
I
I
T
T
G
G
380
|
F
F
L
L
L
L
I
I
Q
Q
A
A
W
W
P
P
E
E
N
N
390
|
R
R
T
T
D
D
L
L
H
H
A
A
F
F
E
E
N
N
L
L
400
|
E
E
I
I
I
I
R
R
G
G
R
R
T
T
K
K
Q
Q
H
H
410
|
G
G
Q
Q
F
F
S
S
L
L
A
A
V
V
V
V
S
S
L
L
420
|
N
N
I
I
T
T
S
S
L
L
G
G
L
L
R
R
S
S
L
L
430
|
K
K
E
E
I
I
S
S
D
D
G
G
D
D
V
V
I
I
I
I
440
|
S
S
G
G
N
N
K
K
N
N
L
L
C
C
Y
Y
A
A
N
N
450
|
T
T
I
I
N
N
W
W
K
K
K
K
L
L
F
F
G
G
T
T
460
|
S
S
G
G
Q
Q
K
K
T
T
K
K
I
I
I
I
S
R
N
N
470
|
R
R
G
G
E
E
N
N
S
S
C
C
K
K
A
A
T
T
G
G
480
|
Q
Q
V
V
C
C
H
H
A
A
L
L
C
C
S
S
P
P
E
E
490
|
G
G
C
C
W
W
G
G
P
P
E
E
P
P
R
R
D
D
C
C
500
|
V
V
S
S
C
C
R
R
N
N
V
V
S
S
R
R
G
G
R
R
510
|
E
E
C
C
V
V
D
D
K
K
H
H
H
H
H
H
H
H
H
H
520
|
H
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
DLD1 cells Colon Homo sapiens (Human) CVCL_0248
SW620 cells Colon Homo sapiens (Human) CVCL_0547
LS1034 cells Colon Homo sapiens (Human) CVCL_1382
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
GEO cells Colon Homo sapiens (Human) CVCL_0271
HCT15 cells Colon Homo sapiens (Human) CVCL_0292
SW480 cells Colon Homo sapiens (Human) CVCL_0546
CaCo2 cells Colon Homo sapiens (Human) CVCL_0025
HCT116 cells Colon Homo sapiens (Human) CVCL_0291
LOVO cells Colon Homo sapiens (Human) CVCL_0399
LS174T cells Colon Homo sapiens (Human) CVCL_1384
SW948 cells Colon Homo sapiens (Human) CVCL_0632
SW403 cells Colon Homo sapiens (Human) CVCL_0545
SW837 cells Colon Homo sapiens (Human) CVCL_1729
T84 cells Colon Homo sapiens (Human) CVCL_0555
SW1463 cells Rectum Homo sapiens (Human) CVCL_1718
H716 cells Ascites Homo sapiens (Human) CVCL_1581
H508 cells Abdominal wall Homo sapiens (Human) CVCL_1564
SNUC2A cells Cecum Homo sapiens (Human) CVCL_1709
COLO678 cells Colon Homo sapiens (Human) CVCL_1129
GP5D cells Colon Homo sapiens (Human) CVCL_1235
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 WST-1 assay
Key Molecule: Epidermal growth factor receptor (EGFR) [35]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Futuximab
 Drug Info 
Molecule Alteration Missense mutation
p.S492R (c.1476C>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 3C09
Mutant Type Structure Method: X-ray diffraction Resolution: 2.80  Å
PDB: 6B3S
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.58
TM score: 0.98774
Amino acid change:
S492R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
L
L
E
E
E
E
310
|
K
K
K
K
V
V
C
C
N
N
G
G
I
I
G
G
I
I
G
G
320
|
E
E
F
F
K
K
D
D
S
S
L
L
S
S
I
I
N
N
A
A
330
|
T
T
N
N
I
I
K
K
H
H
F
F
K
K
N
N
C
C
T
T
340
|
S
S
I
I
S
S
G
G
D
D
L
L
H
H
I
I
L
L
P
P
350
|
V
V
A
A
F
F
R
R
G
G
D
D
S
S
F
F
T
T
H
H
360
|
T
T
P
P
P
P
L
L
D
D
P
P
Q
Q
E
E
L
L
D
D
370
|
I
I
L
L
K
K
T
T
V
V
K
K
E
E
I
I
T
T
G
G
380
|
F
F
L
L
L
L
I
I
Q
Q
A
A
W
W
P
P
E
E
N
N
390
|
R
R
T
T
D
D
L
L
H
H
A
A
F
F
E
E
N
N
L
L
400
|
E
E
I
I
I
I
R
R
G
G
R
R
T
T
K
K
Q
Q
H
H
410
|
G
G
Q
Q
F
F
S
S
L
L
A
A
V
V
V
V
S
S
L
L
420
|
N
N
I
I
T
T
S
S
L
L
G
G
L
L
R
R
S
S
L
L
430
|
K
K
E
E
I
I
S
S
D
D
G
G
D
D
V
V
I
I
I
I
440
|
S
S
G
G
N
N
K
K
N
N
L
L
C
C
Y
Y
A
A
N
N
450
|
T
T
I
I
N
N
W
W
K
K
K
K
L
L
F
F
G
G
T
T
460
|
S
S
G
G
Q
Q
K
K
T
T
K
K
I
I
I
I
S
R
N
N
470
|
R
R
G
G
E
E
N
N
S
S
C
C
K
K
A
A
T
T
G
G
480
|
Q
Q
V
V
C
C
H
H
A
A
L
L
C
C
S
S
P
P
E
E
490
|
G
G
C
C
W
W
G
G
P
P
E
E
P
P
R
R
D
D
C
C
500
|
V
V
S
S
C
C
R
R
N
N
V
V
S
S
R
R
G
G
R
R
510
|
E
E
C
C
V
V
D
D
K
K
H
H
H
H
H
H
H
H
H
H
520
|
H
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Regulation N.A.
In Vitro Model LIM1215 cells Colon Homo sapiens (Human) CVCL_2574
NIH3T3 cells Embryo Homo sapiens (Human) CVCL_0594
EGFR cells N.A. N.A. N.A.
In Vivo Model Male BALB/c nude mouse Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay; FACS assay; Crystal violet staining assay
Mechanism Description Contrary to cetuximab and panitumumab, Sym004 effectively binds to and prevents activation of all the EGFR mutants. Sym004 effectively inhibits proliferation and EGFR downstream signaling in cetuximab-resistant derivatives harboring the S492R and G465R EGFR mutations. Sym004 causes profound and sustained regression in S492R-mutant EGFR and delays tumor growth in G465R-mutant EGFR in vivo.
NMS-P715
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Catenin beta-1 (CTNNB1) [16]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug NMS-P715
 Drug Info 
Molecule Alteration Missense mutation
p.S45F (c.134C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6O9B
Mutant Type Structure Method: X-ray diffraction Resolution: 2.45  Å
PDB: 6O9C
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.23
TM score: 0.84883
Amino acid change:
S45F
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
T
T
T
T
A
A
P
P
S
F
L
L
S
S
G
G
K
K
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
SW48 cells Colon Homo sapiens (Human) CVCL_1724
TOV-21G cells Ovary Homo sapiens (Human) CVCL_3613
HuTu80 cells Small intestine Homo sapiens (Human) CVCL_1301
TOV-112D cells Ovary Homo sapiens (Human) CVCL_3612
LS 174T cells Colon Homo sapiens (Human) CVCL_1384
A427 cells Lung Homo sapiens (Human) CVCL_1055
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Gene set analysis
Experiment for
Drug Resistance		 Cell proliferation assay
Mechanism Description The missense mutation p.S45F (c.134C>T) in gene CTNNB1 cause the sensitivity of NMS-P715 by unusual activation of pro-survival pathway
Panitumumab/Dabrafenib/Trametinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [36]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug Panitumumab/Dabrafenib/Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
SCH772984
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [20]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug SCH772984
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
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Experimental Note Identified from the Human Clinical Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
In Vivo Model Female athymic nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Caspase-Glo 3/7 luminogenic assay
References
Ref 1 Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013 Aug;10(8):472-84. doi: 10.1038/nrclinonc.2013.110. Epub 2013 Jul 9.
Ref 2 Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. Ann Oncol. 2015 Apr;26(4):731-736. doi: 10.1093/annonc/mdv005. Epub 2015 Jan 26.
Ref 3 Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer. Clin Cancer Res. 2017 May 15;23(10):2414-2422. doi: 10.1158/1078-0432.CCR-16-1863. Epub 2016 Oct 25.
Ref 4 Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC).
Ref 5 Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal CancerCancer Discov. 2016 Jan;6(1):36-44. doi: 10.1158/2159-8290.CD-15-0940. Epub 2015 Nov 6.
Ref 6 Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged CancersMol Cancer Ther. 2017 Oct;16(10):2130-2143. doi: 10.1158/1535-7163.MCT-16-0909. Epub 2017 Jul 27.
Ref 7 The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012 Jun 28;486(7404):537-40. doi: 10.1038/nature11219.
Ref 8 KRAS exon 2 mutations influence activity of regorafenib in an SW48-based disease model of colorectal cancerFuture Oncol. 2015;11(13):1919-29. doi: 10.2217/fon.15.97.
Ref 9 AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 MutationsCancer Discov. 2017 May;7(5):478-493. doi: 10.1158/2159-8290.CD-16-1034. Epub 2017 Feb 13.
Ref 10 RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancerCancer Res. 2009 Sep 1;69(17):6839-47. doi: 10.1158/0008-5472.CAN-09-0679. Epub 2009 Aug 25.
Ref 11 Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cellsInt J Cancer. 2013 Nov;133(9):2089-101. doi: 10.1002/ijc.28236. Epub 2013 May 29.
Ref 12 Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)Mol Cancer Ther. 2017 Nov;16(11):2351-2363. doi: 10.1158/1535-7163.MCT-17-0456. Epub 2017 Sep 22.
Ref 13 BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal CancersMol Cancer Ther. 2015 Oct;14(10):2187-97. doi: 10.1158/1535-7163.MCT-15-0262. Epub 2015 Jul 24.
Ref 14 Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198Cancer Res. 2015 Nov 15;75(22):4790-802. doi: 10.1158/0008-5472.CAN-14-3603. Epub 2015 Sep 11.
Ref 15 Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal CancerCancer Res. 2016 Aug 1;76(15):4504-15. doi: 10.1158/0008-5472.CAN-16-0396. Epub 2016 Jun 16.
Ref 16 TTK Inhibitors as a Targeted Therapy for CTNNB1 (Beta-catenin) Mutant CancersMol Cancer Ther. 2017 Nov;16(11):2609-2617. doi: 10.1158/1535-7163.MCT-17-0342. Epub 2017 Jul 27.
Ref 17 Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanomaCancer Cell. 2015 Jan 12;27(1):85-96. doi: 10.1016/j.ccell.2014.11.006. Epub 2014 Dec 11.
Ref 18 Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutationsGenome Res. 2017 Apr;27(4):613-625. doi: 10.1101/gr.213546.116. Epub 2017 Feb 8.
Ref 19 Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomasClin Cancer Res. 2012 May 1;18(9):2515-25. doi: 10.1158/1078-0432.CCR-11-2683. Epub 2012 Mar 5.
Ref 20 Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway OncogenesCancer Cell. 2015 Aug 10;28(2):170-82. doi: 10.1016/j.ccell.2015.07.001.
Ref 21 Discovery of a novel pan-RAF inhibitor with potent anti-tumor activity in preclinical models of BRAF(V600E) mutant cancerLife Sci. 2017 Aug 15;183:37-44. doi: 10.1016/j.lfs.2017.06.021. Epub 2017 Jun 21.
Ref 22 Mouse PDX Trial Suggests Synergy of Concurrent Inhibition of RAF and EGFR in Colorectal Cancer with BRAF or KRAS MutationsClin Cancer Res. 2017 Sep 15;23(18):5547-5560. doi: 10.1158/1078-0432.CCR-16-3250. Epub 2017 Jun 13.
Ref 23 MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutationsSci Transl Med. 2016 Feb 3;8(324):324ra14. doi: 10.1126/scitranslmed.aad5640.
Ref 24 Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53Cancer Res. 2015 Sep 15;75(18):3842-52. doi: 10.1158/0008-5472.CAN-13-1079. Epub 2015 Aug 20.
Ref 25 A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic interventionCancer Cell. 2013 Jul 8;24(1):15-29. doi: 10.1016/j.ccr.2013.05.014.
Ref 26 RAF inhibitors that evade paradoxical MAPK pathway activationNature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14.
Ref 27 Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinasesNature. 2016 Jul 7;535(7610):148-52. doi: 10.1038/nature18621. Epub 2016 Jun 29.
Ref 28 An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF SignalingCancer Cell. 2016 Sep 12;30(3):485-498. doi: 10.1016/j.ccell.2016.06.024. Epub 2016 Aug 11.
Ref 29 Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancerCancer Res. 2012 Feb 1;72(3):779-89. doi: 10.1158/0008-5472.CAN-11-2941. Epub 2011 Dec 16.
Ref 30 Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal CancerN Engl J Med. 2019 Oct 24;381(17):1632-1643. doi: 10.1056/NEJMoa1908075. Epub 2019 Sep 30.
Ref 31 Clinical responses to ERK inhibition in BRAF(V600E)-mutant colorectal cancer predicted using a computational modelNPJ Syst Biol Appl. 2017 Jun 2;3:14. doi: 10.1038/s41540-017-0016-1. eCollection 2017.
Ref 32 HRAS G13D, a new mutation implicated in the resistance to anti-EGFR therapies in colorectal cancer, a case reportInt J Colorectal Dis. 2016 Jun;31(6):1245-6. doi: 10.1007/s00384-015-2448-7. Epub 2015 Nov 12.
Ref 33 Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinomaCancer Sci. 2010 Feb;101(2):530-5. doi: 10.1111/j.1349-7006.2009.01418.x. Epub 2009 Oct 28.
Ref 34 Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal CancerCancer Discov. 2015 Jun;5(6):598-609. doi: 10.1158/2159-8290.CD-14-1432. Epub 2015 May 11.
Ref 35 The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal CancerClin Cancer Res. 2016 Jul 1;22(13):3260-7. doi: 10.1158/1078-0432.CCR-15-2400. Epub 2016 Feb 17.
Ref 36 Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF(V600E)-Mutant Colorectal CancerCancer Discov. 2018 Apr;8(4):428-443. doi: 10.1158/2159-8290.CD-17-1226. Epub 2018 Feb 5.

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