Drug Information

Drug (ID: DG01764) and It's Reported Resistant Information
Name
Futuximab
Synonyms
Futuximab
    Click to Show/Hide
Type(s) of Resistant Mechanism of This Drug
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
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) [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.R451C (c.1351C>T)
 Molecule Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.K467T (c.1400A>C)
 Molecule Info 
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.
Colorectal cancer [ICD-11: 2B91]
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) [2]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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) [1]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.R451C (c.1351C>T)
 Molecule Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.G465R (c.1393G>A)
 Molecule Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.K467T (c.1400A>C)
 Molecule Info 
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.
References
Ref 1 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 2 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.

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