Disease Information

General Information of the Disease (ID: DIS00105)
Name
Metastatic colorectal cancer
ICD
ICD-11: 2D85
Resistance Map
Type(s) of Resistant Mechanism of This Disease with Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
2 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
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Resistant Drug Cetuximab
 Drug Info 
Molecule Alteration Missense mutation
p.S492R
 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
Experiment for
Molecule Alteration		 Circulating-free DNA assay; Standard-of-care sequencing assay
Mechanism Description K-RAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs).
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase KRas (KRAS) [2]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
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 Vitro Model DiFi cells Colon Homo sapiens (Human) CVCL_6895
DiFi-R cells Colon Homo sapiens (Human) CVCL_A2BW
Lim1215-R cells Colon Homo sapiens (Human) CVCL_1736
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 FISH analysis; Sanger sequencing assay
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description Nevertheless, our functional analysis in cell models show that kRAS mutations are causally responsible for acquired resistance to cetuximab.
Key Molecule: GTPase Nras (NRAS) [3]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Resistant Drug Cetuximab
 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
Cell Pathway Regulation EGFR/RAS signaling pathway Inhibition 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 biopsies assay; Functional analyses of cell populations assay
Mechanism Description Acquired resistance to EGFR blockade is driven by the emergence of kRAS/NRAS mutations or the development of EGFR extracellular domain (ECD) variants, which impair antibody binding.
Panitumumab
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: Epidermal growth factor receptor (EGFR) [1]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Missense mutation
p.S492R
 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
Experiment for
Molecule Alteration		 Circulating-free DNA assay; Standard-of-care sequencing assay
Mechanism Description K-RAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs).
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [3]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
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
Cell Pathway Regulation EGFR/RAS signaling pathway Inhibition 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 biopsies assay; Functional analyses of cell populations assay
Mechanism Description Acquired resistance to EGFR blockade is driven by the emergence of kRAS/NRAS mutations or the development of EGFR extracellular domain (ECD) variants, which impair antibody binding.
References
Ref 1 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 2 Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012 Jun 28;486(7404):532-6. doi: 10.1038/nature11156.
Ref 3 Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer. Nat Commun. 2016 Dec 8;7:13665. doi: 10.1038/ncomms13665.

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