Disease Information

General Information of the Disease (ID: DIS00006)
Name
Solid tumour/cancer
ICD
ICD-11: 2A00-2F9Z
Resistance Map
Type(s) of Resistant Mechanism of This Disease
  ADTT: Aberration of the Drug's Therapeutic Target
  DISM: Drug Inactivation by Structure Modification
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  RTDM: Regulation by the Disease Microenvironment
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
35 drug(s) in total
Click to Show/Hide the Full List of Drugs
Avapritinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
M230 cells Skin Homo sapiens (Human) CVCL_D749
Experiment for
Molecule Alteration		 PCR
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [2]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.D842V (c.2525A>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
M-07e cells Peripheral blood Homo sapiens (Human) CVCL_2106
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
Chinese hamster ovary (CHO)-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Enzyme-linked immunosorbent assay; Cellular proliferation test assay
Axitinib
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: Tyrosine-protein kinase ABL1 (ABL1) [3]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I (c.944C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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130
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140
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160
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170
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180
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R
190
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Y
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200
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L
L
Y
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V
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210
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R
R
F
F
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220
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H
H
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230
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240
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N
K
K
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250
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T
260
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270
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280
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290
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300
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L
L
L
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G
G
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340
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350
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N
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360
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370
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N
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380
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390
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400
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410
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow N.A.
Mechanism Description The missense mutation p.T315I (c.944C>T) in gene ABL1 cause the sensitivity of Axitinib by aberration of the drug's therapeutic target
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T670I (c.2009C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.25  Å
PDB: 6HH1
Mutant Type Structure Method: X-ray diffraction Resolution: 2.40  Å
PDB: 8PQG
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.88
TM score: 0.9084
Amino acid change:
T670I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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600
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610
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630
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640
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650
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A
660
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670
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I
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E
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Y
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C
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Y
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G
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680
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F
690
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700
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710
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720
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730
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740
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750
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770
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L
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F
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Y
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V
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A
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K
G
G
780
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M
M
A
A
F
F
L
L
A
A
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N
C
C
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I
790
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A
A
A
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R
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800
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C
810
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D
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G
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A
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820
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A
830
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840
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Y
T
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E
850
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860
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F
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P
870
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F
880
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K
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K
E
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M
890
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M
900
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D
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A
910
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920
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930
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H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.V559D (c.1676T>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.V559A (c.1676T>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.V559G (c.1676T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.L576P (c.1727T>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.V654A (c.1961T>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.A829P (c.2485G>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Binimetinib
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: MAPK/ERK kinase 1 (MEK1) [5]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Binimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.V211D (c.632T>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
Phoenix AMPHO cells Fetal kidney Homo sapiens (Human) CVCL_H716
In Vivo Model NOD scid gamma xenograft model Mus musculus
Experiment for
Molecule Alteration		 Single cell sequencing assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Hras (HRAS) [6]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Binimetinib
 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 T24 cells Bladder Homo sapiens (Human) CVCL_0554
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
RL952 cells Endometrium Homo sapiens (Human) CVCL_0505
NCI-H1915 cells Lung Homo sapiens (Human) CVCL_1505
KYSE-30 cells Esophagus Homo sapiens (Human) CVCL_1351
KNS62 cells Brain Homo sapiens (Human) CVCL_1335
HCC78 cells Pleural effusion Homo sapiens (Human) CVCL_2061
HCC44 cells Lung Homo sapiens (Human) CVCL_2060
CAL-12T cells Lung Homo sapiens (Human) CVCL_1105
In Vivo Model CB17 SCID-/- mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
Key Molecule: GTPase Hras (HRAS) [6]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Binimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61R (c.182A>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.24  Å
PDB: 7F68
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.46
TM score: 0.94384
Amino acid change:
Q61R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
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
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
R
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
D
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
-
L
-
N
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model T24 cells Bladder Homo sapiens (Human) CVCL_0554
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
RL952 cells Endometrium Homo sapiens (Human) CVCL_0505
NCI-H1915 cells Lung Homo sapiens (Human) CVCL_1505
KYSE-30 cells Esophagus Homo sapiens (Human) CVCL_1351
KNS62 cells Brain Homo sapiens (Human) CVCL_1335
HCC78 cells Pleural effusion Homo sapiens (Human) CVCL_2061
HCC44 cells Lung Homo sapiens (Human) CVCL_2060
CAL-12T cells Lung Homo sapiens (Human) CVCL_1105
In Vivo Model CB17 SCID-/- mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
Brigatinib
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: ALK tyrosine kinase receptor (ALK) [7]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G1202R (c.3604G>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Thymidine Incorporation assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [7]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G1269A (c.3806G>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 4TT7
Mutant Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 4ANL
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.56
TM score: 0.97543
Amino acid change:
G1269A
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
1070
|
-
M
-
A
-
H
-
H
-
H
-
H
-
H
-
H
-
D
-
Y
1080
|
-
G
-
I
-
P
-
T
-
T
-
E
-
N
-
L
-
Y
-
F
1090
|
-
Q
-
G
-
S
-
N
M
P
N
N
Y
Y
C
C
F
F
A
A
1100
|
G
G
K
K
T
T
S
S
S
S
I
I
S
S
D
D
L
L
K
K
1110
|
E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
|
R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
|
V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
|
N
N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
|
K
K
T
T
L
L
P
P
E
E
V
V
C
C
S
S
E
E
Q
Q
1160
|
D
D
E
E
L
L
D
D
F
F
L
L
M
M
E
E
A
A
L
L
1170
|
I
I
I
I
S
S
K
K
F
F
N
N
H
H
Q
Q
N
N
I
I
1180
|
V
V
R
R
C
C
I
I
G
G
V
V
S
S
L
L
Q
Q
S
S
1190
|
L
L
P
P
R
R
F
F
I
I
L
L
L
L
E
E
L
L
M
M
1200
|
A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
|
E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
|
S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
|
A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
|
L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
|
I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
|
P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
A
1270
|
D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
|
A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
|
M
M
L
L
P
P
V
V
K
K
W
W
M
M
P
P
P
P
E
E
1300
|
A
A
F
F
M
M
E
E
G
G
I
I
F
F
T
T
S
S
K
K
1310
|
T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
|
W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
|
Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
|
E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
|
P
P
P
P
K
K
N
N
C
C
P
P
G
G
P
P
V
V
Y
Y
1360
|
R
R
I
I
M
M
T
T
Q
Q
C
C
W
W
Q
Q
H
H
Q
Q
1370
|
P
P
E
E
D
D
R
R
P
P
N
N
F
F
A
A
I
I
I
I
1380
|
L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
|
P
P
D
D
V
V
I
I
N
N
T
T
A
A
L
L
P
P
I
I
1400
|
E
E
Y
Y
G
G
P
P
L
L
V
V
E
E
E
E
E
E
E
E
1410
|
K
K
L
V
E
-
H
-
H
-
H
-
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model IMR-32 cells Abdomen Homo sapiens (Human) CVCL_0346
PC12 cells Adrenal gland Rattus norvegicus (Rat) CVCL_0481
CLB-PE cells Brain Homo sapiens (Human) CVCL_9534
CLB-GE cells Bone marrow Homo sapiens (Human) CVCL_9530
CLB-BAR cells Brain Homo sapiens (Human) CVCL_9519
In Vivo Model Female Balbc/nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Resazurin assay
Key Molecule: ALK tyrosine kinase receptor (ALK) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L (c.3520T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 4FNW
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.34
TM score: 0.99391
Amino acid change:
F1174L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
M
-
1070
|
Q
-
M
-
E
-
L
-
Q
-
S
-
P
-
E
-
Y
-
K
-
1080
|
L
-
S
-
K
-
L
-
R
R
T
T
S
S
T
T
I
I
M
M
1090
|
T
T
D
D
Y
Y
N
N
P
P
N
N
Y
Y
C
S
F
F
A
A
1100
|
G
G
K
K
T
T
S
S
S
S
I
I
S
S
D
D
L
L
K
K
1110
|
E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
|
R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
|
V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
|
N
N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
|
K
K
T
T
L
L
P
P
E
E
V
V
C
C
S
S
E
E
Q
Q
1160
|
D
D
E
E
L
L
D
D
F
F
L
L
M
M
E
E
A
A
L
L
1170
|
I
I
I
I
S
S
K
K
F
L
N
N
H
H
Q
Q
N
N
I
I
1180
|
V
V
R
R
C
C
I
I
G
G
V
V
S
S
L
L
Q
Q
S
S
1190
|
L
L
P
P
R
R
F
F
I
I
L
L
L
L
E
E
L
L
M
M
1200
|
A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
|
E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
|
S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
|
A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
|
L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
|
I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
|
P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
G
1270
|
D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
|
A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
|
M
M
L
L
P
P
V
V
K
K
W
W
M
M
P
P
P
P
E
E
1300
|
A
A
F
F
M
M
E
E
G
G
I
I
F
F
T
T
S
S
K
K
1310
|
T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
|
W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
|
Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
|
E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
|
P
P
P
P
K
K
N
N
C
C
P
P
G
G
P
P
V
V
Y
Y
1360
|
R
R
I
I
M
M
T
T
Q
Q
C
C
W
W
Q
Q
H
H
Q
Q
1370
|
P
P
E
E
D
D
R
R
P
P
N
N
F
F
A
A
I
I
I
I
1380
|
L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
|
P
P
D
D
V
V
I
I
N
N
T
T
A
A
L
L
P
P
I
I
1400
|
E
E
Y
Y
G
G
P
P
L
L
V
V
E
E
E
E
E
E
E
E
1410
|
K
K
V
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model IMR-32 cells Abdomen Homo sapiens (Human) CVCL_0346
CLB-GE cells Bone marrow Homo sapiens (Human) CVCL_9530
CLB-BAR cells Brain Homo sapiens (Human) CVCL_9519
In Vivo Model Female Balbc/nude mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.F1174L (c.3520T>C) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target
Key Molecule: ALK tyrosine kinase receptor (ALK) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G1128A (c.3383G>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model IMR-32 cells Abdomen Homo sapiens (Human) CVCL_0346
CLB-GE cells Bone marrow Homo sapiens (Human) CVCL_9530
CLB-BAR cells Brain Homo sapiens (Human) CVCL_9519
In Vivo Model Female Balbc/nude mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.G1128A (c.3383G>C) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target
Key Molecule: ALK tyrosine kinase receptor (ALK) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.I1171N (c.3512T>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model IMR-32 cells Abdomen Homo sapiens (Human) CVCL_0346
CLB-GE cells Bone marrow Homo sapiens (Human) CVCL_9530
CLB-BAR cells Brain Homo sapiens (Human) CVCL_9519
In Vivo Model Female Balbc/nude mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.I1171N (c.3512T>A) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target
Key Molecule: ALK tyrosine kinase receptor (ALK) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.R1192P (c.3575G>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model IMR-32 cells Abdomen Homo sapiens (Human) CVCL_0346
CLB-GE cells Bone marrow Homo sapiens (Human) CVCL_9530
CLB-BAR cells Brain Homo sapiens (Human) CVCL_9519
In Vivo Model Female Balbc/nude mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.R1192P (c.3575G>C) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target
Key Molecule: ALK tyrosine kinase receptor (ALK) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.F1245C (c.3734T>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model IMR-32 cells Abdomen Homo sapiens (Human) CVCL_0346
CLB-GE cells Bone marrow Homo sapiens (Human) CVCL_9530
CLB-BAR cells Brain Homo sapiens (Human) CVCL_9519
In Vivo Model Female Balbc/nude mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.F1245C (c.3734T>G) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target
Key Molecule: ALK tyrosine kinase receptor (ALK) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.R1275Q (c.3824G>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model IMR-32 cells Abdomen Homo sapiens (Human) CVCL_0346
CLB-GE cells Bone marrow Homo sapiens (Human) CVCL_9530
CLB-BAR cells Brain Homo sapiens (Human) CVCL_9519
In Vivo Model Female Balbc/nude mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.R1275Q (c.3824G>A) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target
Key Molecule: ALK tyrosine kinase receptor (ALK) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.Y1278S (c.3833A>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model IMR-32 cells Abdomen Homo sapiens (Human) CVCL_0346
CLB-GE cells Bone marrow Homo sapiens (Human) CVCL_9530
CLB-BAR cells Brain Homo sapiens (Human) CVCL_9519
In Vivo Model Female Balbc/nude mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.Y1278S (c.3833A>C) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [9]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.L858R (c.2573T>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.47  Å
PDB: 2ITV
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.90001
Amino acid change:
L858R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
M
-
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
T
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
R
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
-
Q
-
G
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
U937 cells Blood Homo sapiens (Human) CVCL_0007
H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
SUP-M2 cells Colon Homo sapiens (Human) CVCL_2209
KARPAS-299 cells Peripheral blood Homo sapiens (Human) CVCL_1324
SU-DHL-1 cells Pleural effusion Homo sapiens (Human) CVCL_0538
L-82 cells Pleural effusion Homo sapiens (Human) CVCL_2098
HCC78 cells Pleural effusion Homo sapiens (Human) CVCL_2061
H838 cells Lymph node Homo sapiens (Human) CVCL_1594
H-4-II-E cells Liver Rattus norvegicus (Rat) CVCL_0284
H358 cells Lung Homo sapiens (Human) CVCL_1559
H2228 cells Lung Homo sapiens (Human) CVCL_1543
DEL cells Pleural effusion Homo sapiens (Human) CVCL_1170
In Vivo Model SCID beige mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Brigatinib is the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses.
Key Molecule: Epidermal growth factor receptor (EGFR) [9]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration IF-deletion
p.E746_A750delELREA (c.2236_2250del15)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
U937 cells Blood Homo sapiens (Human) CVCL_0007
H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
SUP-M2 cells Colon Homo sapiens (Human) CVCL_2209
KARPAS-299 cells Peripheral blood Homo sapiens (Human) CVCL_1324
SU-DHL-1 cells Pleural effusion Homo sapiens (Human) CVCL_0538
L-82 cells Pleural effusion Homo sapiens (Human) CVCL_2098
HCC78 cells Pleural effusion Homo sapiens (Human) CVCL_2061
H838 cells Lymph node Homo sapiens (Human) CVCL_1594
H-4-II-E cells Liver Rattus norvegicus (Rat) CVCL_0284
H358 cells Lung Homo sapiens (Human) CVCL_1559
H2228 cells Lung Homo sapiens (Human) CVCL_1543
DEL cells Pleural effusion Homo sapiens (Human) CVCL_1170
In Vivo Model SCID beige mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Brigatinib is the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses.
Cabozantinib
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: Mast/stem cell growth factor receptor Kit (KIT) [10]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model 32D cells Bone marrow Homo sapiens (Human) CVCL_0118
In Vivo Model Female Balb/cA-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.D816V (c.2447A>T) in gene KIT cause the resistance of Cabozantinib by aberration of the drug's therapeutic target
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Hepatocyte growth factor receptor (MET) [11]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.Y1003F (c.3008A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
WEHI-3 cells Peripheral blood Mus musculus (Mouse) CVCL_3622
Hs746T cells Skeletal muscle Homo sapiens (Human) CVCL_0333
Gp2-293 cells Fetal kidney Homo sapiens (Human) CVCL_WI48
Experiment for
Molecule Alteration		 Direct sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Hepatocyte growth factor receptor (MET) [11]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.D1010Y (c.3028G>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
WEHI-3 cells Peripheral blood Mus musculus (Mouse) CVCL_3622
Hs746T cells Skeletal muscle Homo sapiens (Human) CVCL_0333
Gp2-293 cells Fetal kidney Homo sapiens (Human) CVCL_WI48
Experiment for
Molecule Alteration		 Direct sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Hepatocyte growth factor receptor (MET) [12]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.D1228V (c.3683A>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.71  Å
PDB: 5HNI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.67  Å
PDB: 6SDC
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.85
TM score: 0.88477
Amino acid change:
D1228V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
G
-
D
1040
|
-
S
-
D
-
I
-
S
-
S
-
P
-
L
-
L
-
Q
N
N
1050
|
T
T
V
V
H
H
I
I
D
D
L
L
S
S
A
A
L
L
N
N
1060
|
P
P
E
E
L
L
V
V
Q
Q
A
A
V
V
Q
Q
H
H
V
V
1070
|
V
V
I
I
G
G
P
P
S
S
S
S
L
L
I
I
V
V
H
H
1080
|
F
F
N
N
E
E
V
V
I
I
G
G
R
R
G
G
H
H
F
F
1090
|
G
G
C
C
V
V
Y
Y
H
H
G
G
T
T
L
L
L
L
D
D
1100
|
N
N
D
D
G
G
K
K
K
K
I
I
H
H
C
C
A
A
V
V
1110
|
K
K
S
S
L
L
N
N
R
R
I
I
T
T
D
D
I
I
G
G
1120
|
E
E
V
V
S
S
Q
Q
F
F
L
L
T
T
E
E
G
G
I
I
1130
|
I
I
M
M
K
K
D
D
F
F
S
S
H
H
P
P
N
N
V
V
1140
|
L
L
S
S
L
L
L
L
G
G
I
I
C
C
L
L
R
R
S
S
1150
|
E
E
G
G
S
S
P
P
L
L
V
V
V
V
L
L
P
P
Y
Y
1160
|
M
M
K
K
H
H
G
G
D
D
L
L
R
R
N
N
F
F
I
I
1170
|
R
R
N
N
E
E
T
T
H
H
N
N
P
P
T
T
V
V
K
K
1180
|
D
D
L
L
I
I
G
G
F
F
G
G
L
L
Q
Q
V
V
A
A
1190
|
K
K
G
G
M
M
K
K
F
Y
L
L
A
A
S
S
K
K
K
K
1200
|
F
F
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
1210
|
C
C
M
M
L
L
D
D
E
E
K
K
F
F
T
T
V
V
K
K
1220
|
V
V
A
A
D
D
F
F
G
G
L
L
A
A
R
R
D
V
M
M
1230
|
Y
Y
D
D
K
K
E
E
F
Y
D
Y
S
S
V
V
H
H
N
N
1240
|
K
K
T
T
G
G
A
A
K
K
L
L
P
P
V
V
K
K
W
W
1250
|
M
M
A
A
L
L
E
E
S
S
L
L
Q
Q
T
T
Q
Q
K
K
1260
|
F
F
T
T
T
T
K
K
S
S
D
D
V
V
W
W
S
S
F
F
1270
|
G
G
V
V
L
L
L
L
W
W
E
E
L
L
M
M
T
T
R
R
1280
|
G
G
A
A
P
P
P
P
Y
Y
P
P
D
D
V
V
N
N
T
T
1290
|
F
F
D
D
I
I
T
T
V
V
Y
Y
L
L
L
L
Q
Q
G
G
1300
|
R
R
R
R
L
L
L
L
Q
Q
P
P
E
E
Y
Y
C
C
P
P
1310
|
D
D
P
P
L
L
Y
Y
E
E
V
V
M
M
L
L
K
K
C
C
1320
|
W
W
H
H
P
P
K
K
A
A
E
E
M
M
R
R
P
P
S
S
1330
|
F
F
S
S
E
E
L
L
V
V
S
S
R
R
I
I
S
S
A
A
1340
|
I
I
F
F
S
S
T
T
F
F
I
I
G
G
E
-
H
-
Y
-
1350
|
V
-
H
-
V
-
N
-
A
-
T
-
Y
-
V
-
N
-
V
-
1360
|
K
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description There is a patient with metastatic NSCLC with MET-mediated resistance to EGFR TKI who responded to treatment with a type I MET inhibitor, savolitinib, given in combination with a third-generation EGFR inhibitor, osimertinib. The patient then developed acquired resistance mediated by a novel MET kinase domain mutation.
Key Molecule: Hepatocyte growth factor receptor (MET) [13]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.Y1230H (c.3688T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.71  Å
PDB: 5HNI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.97  Å
PDB: 5HLW
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.65
TM score: 0.96625
Amino acid change:
Y1230H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
N
-
1050
|
T
-
V
-
H
-
I
-
D
-
L
-
S
-
A
A
L
L
N
N
1060
|
P
P
E
E
L
L
V
V
Q
Q
A
A
V
V
Q
Q
H
H
V
V
1070
|
V
V
I
I
G
G
P
P
S
S
S
S
L
L
I
I
V
V
H
H
1080
|
F
F
N
N
E
E
V
V
I
I
G
G
R
R
G
G
H
H
F
F
1090
|
G
G
C
C
V
V
Y
Y
H
H
G
G
T
T
L
L
L
L
D
D
1100
|
N
N
D
D
G
G
K
K
K
K
I
I
H
H
C
C
A
A
V
V
1110
|
K
K
S
S
L
L
N
N
R
R
I
I
T
T
D
D
I
I
G
G
1120
|
E
E
V
V
S
S
Q
Q
F
F
L
L
T
T
E
E
G
G
I
I
1130
|
I
I
M
M
K
K
D
D
F
F
S
S
H
H
P
P
N
N
V
V
1140
|
L
L
S
S
L
L
L
L
G
G
I
I
C
C
L
L
R
R
S
S
1150
|
E
E
G
G
S
S
P
P
L
L
V
V
V
V
L
L
P
P
Y
Y
1160
|
M
M
K
K
H
H
G
G
D
D
L
L
R
R
N
N
F
F
I
I
1170
|
R
R
N
N
E
E
T
T
H
H
N
N
P
P
T
T
V
V
K
K
1180
|
D
D
L
L
I
I
G
G
F
F
G
G
L
L
Q
Q
V
V
A
A
1190
|
K
K
G
G
M
M
K
K
F
Y
L
L
A
A
S
S
K
K
K
K
1200
|
F
F
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
1210
|
C
C
M
M
L
L
D
D
E
E
K
K
F
F
T
T
V
V
K
K
1220
|
V
V
A
A
D
D
F
F
G
G
L
L
A
A
R
R
D
D
M
M
1230
|
Y
H
D
D
K
K
E
E
F
Y
D
Y
S
S
V
V
H
H
N
N
1240
|
K
K
T
T
G
G
A
A
K
K
L
L
P
P
V
V
K
K
W
W
1250
|
M
M
A
A
L
L
E
E
S
S
L
L
Q
Q
T
T
Q
Q
K
K
1260
|
F
F
T
T
T
T
K
K
S
S
D
D
V
V
W
W
S
S
F
F
1270
|
G
G
V
V
L
L
L
L
W
W
E
E
L
L
M
M
T
T
R
R
1280
|
G
G
A
A
P
P
P
P
Y
Y
P
P
D
D
V
V
N
N
T
T
1290
|
F
F
D
D
I
I
T
T
V
V
Y
Y
L
L
L
L
Q
Q
G
G
1300
|
R
R
R
R
L
L
L
L
Q
Q
P
P
E
E
Y
Y
C
C
P
P
1310
|
D
D
P
P
L
L
Y
Y
E
E
V
V
M
M
L
L
K
K
C
C
1320
|
W
W
H
H
P
P
K
K
A
A
E
E
M
M
R
R
P
P
S
S
1330
|
F
F
S
S
E
E
L
L
V
V
S
S
R
R
I
I
S
S
A
A
1340
|
I
I
F
F
S
S
T
T
F
F
I
I
G
G
E
E
H
H
Y
Y
1350
|
V
V
H
H
V
V
N
N
A
A
T
T
Y
-
V
-
N
-
V
-
1360
|
K
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model NIH3T3 cells Embryo Homo sapiens (Human) CVCL_0594
In Vivo Model Athymic female mouse PDX model Mus musculus
Experiment for
Drug Resistance		 MTS assay
Mechanism Description MET mutations Y1248H and D1246N are resistance mechanisms for type I MET-TKIs. NIH3T3 cells expressing either mutation showed resistance to both INC280 and crizotinib but not cabozantinib, indicating the potential of sequential use of MET inhibitors may lead to a more durable response.
Key Molecule: Hepatocyte growth factor receptor (MET) [13]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.D1228N (c.3682G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model NIH3T3 cells Embryo Homo sapiens (Human) CVCL_0594
In Vivo Model Athymic female mouse PDX model Mus musculus
Experiment for
Drug Resistance		 MTS assay
Mechanism Description MET mutations Y1248H and D1246N are resistance mechanisms for type I MET-TKIs. NIH3T3 cells expressing either mutation showed resistance to both INC280 and crizotinib but not cabozantinib, indicating the potential of sequential use of MET inhibitors may lead to a more durable response.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [14]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.V299L (c.895G>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ph+ALL cells N.A. N.A. N.A.
Mechanism Description The missense mutation p.V299L (c.895G>C) in gene ABL1 cause the sensitivity of Cabozantinib by aberration of the drug's therapeutic target
Capmatinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Hepatocyte growth factor receptor (MET) [12]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Capmatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D1228V (c.3683A>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.71  Å
PDB: 5HNI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.67  Å
PDB: 6SDC
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.85
TM score: 0.88477
Amino acid change:
D1228V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
G
-
D
1040
|
-
S
-
D
-
I
-
S
-
S
-
P
-
L
-
L
-
Q
N
N
1050
|
T
T
V
V
H
H
I
I
D
D
L
L
S
S
A
A
L
L
N
N
1060
|
P
P
E
E
L
L
V
V
Q
Q
A
A
V
V
Q
Q
H
H
V
V
1070
|
V
V
I
I
G
G
P
P
S
S
S
S
L
L
I
I
V
V
H
H
1080
|
F
F
N
N
E
E
V
V
I
I
G
G
R
R
G
G
H
H
F
F
1090
|
G
G
C
C
V
V
Y
Y
H
H
G
G
T
T
L
L
L
L
D
D
1100
|
N
N
D
D
G
G
K
K
K
K
I
I
H
H
C
C
A
A
V
V
1110
|
K
K
S
S
L
L
N
N
R
R
I
I
T
T
D
D
I
I
G
G
1120
|
E
E
V
V
S
S
Q
Q
F
F
L
L
T
T
E
E
G
G
I
I
1130
|
I
I
M
M
K
K
D
D
F
F
S
S
H
H
P
P
N
N
V
V
1140
|
L
L
S
S
L
L
L
L
G
G
I
I
C
C
L
L
R
R
S
S
1150
|
E
E
G
G
S
S
P
P
L
L
V
V
V
V
L
L
P
P
Y
Y
1160
|
M
M
K
K
H
H
G
G
D
D
L
L
R
R
N
N
F
F
I
I
1170
|
R
R
N
N
E
E
T
T
H
H
N
N
P
P
T
T
V
V
K
K
1180
|
D
D
L
L
I
I
G
G
F
F
G
G
L
L
Q
Q
V
V
A
A
1190
|
K
K
G
G
M
M
K
K
F
Y
L
L
A
A
S
S
K
K
K
K
1200
|
F
F
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
1210
|
C
C
M
M
L
L
D
D
E
E
K
K
F
F
T
T
V
V
K
K
1220
|
V
V
A
A
D
D
F
F
G
G
L
L
A
A
R
R
D
V
M
M
1230
|
Y
Y
D
D
K
K
E
E
F
Y
D
Y
S
S
V
V
H
H
N
N
1240
|
K
K
T
T
G
G
A
A
K
K
L
L
P
P
V
V
K
K
W
W
1250
|
M
M
A
A
L
L
E
E
S
S
L
L
Q
Q
T
T
Q
Q
K
K
1260
|
F
F
T
T
T
T
K
K
S
S
D
D
V
V
W
W
S
S
F
F
1270
|
G
G
V
V
L
L
L
L
W
W
E
E
L
L
M
M
T
T
R
R
1280
|
G
G
A
A
P
P
P
P
Y
Y
P
P
D
D
V
V
N
N
T
T
1290
|
F
F
D
D
I
I
T
T
V
V
Y
Y
L
L
L
L
Q
Q
G
G
1300
|
R
R
R
R
L
L
L
L
Q
Q
P
P
E
E
Y
Y
C
C
P
P
1310
|
D
D
P
P
L
L
Y
Y
E
E
V
V
M
M
L
L
K
K
C
C
1320
|
W
W
H
H
P
P
K
K
A
A
E
E
M
M
R
R
P
P
S
S
1330
|
F
F
S
S
E
E
L
L
V
V
S
S
R
R
I
I
S
S
A
A
1340
|
I
I
F
F
S
S
T
T
F
F
I
I
G
G
E
-
H
-
Y
-
1350
|
V
-
H
-
V
-
N
-
A
-
T
-
Y
-
V
-
N
-
V
-
1360
|
K
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description There is a patient with metastatic NSCLC with MET-mediated resistance to EGFR TKI who responded to treatment with a type I MET inhibitor, savolitinib, given in combination with a third-generation EGFR inhibitor, osimertinib. The patient then developed acquired resistance mediated by a novel MET kinase domain mutation.
Key Molecule: Hepatocyte growth factor receptor (MET) [13]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Capmatinib
 Drug Info 
Molecule Alteration Missense mutation
p.Y1230H (c.3688T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.71  Å
PDB: 5HNI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.97  Å
PDB: 5HLW
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.65
TM score: 0.96625
Amino acid change:
Y1230H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
N
-
1050
|
T
-
V
-
H
-
I
-
D
-
L
-
S
-
A
A
L
L
N
N
1060
|
P
P
E
E
L
L
V
V
Q
Q
A
A
V
V
Q
Q
H
H
V
V
1070
|
V
V
I
I
G
G
P
P
S
S
S
S
L
L
I
I
V
V
H
H
1080
|
F
F
N
N
E
E
V
V
I
I
G
G
R
R
G
G
H
H
F
F
1090
|
G
G
C
C
V
V
Y
Y
H
H
G
G
T
T
L
L
L
L
D
D
1100
|
N
N
D
D
G
G
K
K
K
K
I
I
H
H
C
C
A
A
V
V
1110
|
K
K
S
S
L
L
N
N
R
R
I
I
T
T
D
D
I
I
G
G
1120
|
E
E
V
V
S
S
Q
Q
F
F
L
L
T
T
E
E
G
G
I
I
1130
|
I
I
M
M
K
K
D
D
F
F
S
S
H
H
P
P
N
N
V
V
1140
|
L
L
S
S
L
L
L
L
G
G
I
I
C
C
L
L
R
R
S
S
1150
|
E
E
G
G
S
S
P
P
L
L
V
V
V
V
L
L
P
P
Y
Y
1160
|
M
M
K
K
H
H
G
G
D
D
L
L
R
R
N
N
F
F
I
I
1170
|
R
R
N
N
E
E
T
T
H
H
N
N
P
P
T
T
V
V
K
K
1180
|
D
D
L
L
I
I
G
G
F
F
G
G
L
L
Q
Q
V
V
A
A
1190
|
K
K
G
G
M
M
K
K
F
Y
L
L
A
A
S
S
K
K
K
K
1200
|
F
F
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
1210
|
C
C
M
M
L
L
D
D
E
E
K
K
F
F
T
T
V
V
K
K
1220
|
V
V
A
A
D
D
F
F
G
G
L
L
A
A
R
R
D
D
M
M
1230
|
Y
H
D
D
K
K
E
E
F
Y
D
Y
S
S
V
V
H
H
N
N
1240
|
K
K
T
T
G
G
A
A
K
K
L
L
P
P
V
V
K
K
W
W
1250
|
M
M
A
A
L
L
E
E
S
S
L
L
Q
Q
T
T
Q
Q
K
K
1260
|
F
F
T
T
T
T
K
K
S
S
D
D
V
V
W
W
S
S
F
F
1270
|
G
G
V
V
L
L
L
L
W
W
E
E
L
L
M
M
T
T
R
R
1280
|
G
G
A
A
P
P
P
P
Y
Y
P
P
D
D
V
V
N
N
T
T
1290
|
F
F
D
D
I
I
T
T
V
V
Y
Y
L
L
L
L
Q
Q
G
G
1300
|
R
R
R
R
L
L
L
L
Q
Q
P
P
E
E
Y
Y
C
C
P
P
1310
|
D
D
P
P
L
L
Y
Y
E
E
V
V
M
M
L
L
K
K
C
C
1320
|
W
W
H
H
P
P
K
K
A
A
E
E
M
M
R
R
P
P
S
S
1330
|
F
F
S
S
E
E
L
L
V
V
S
S
R
R
I
I
S
S
A
A
1340
|
I
I
F
F
S
S
T
T
F
F
I
I
G
G
E
E
H
H
Y
Y
1350
|
V
V
H
H
V
V
N
N
A
A
T
T
Y
-
V
-
N
-
V
-
1360
|
K
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model NIH3T3 cells Embryo Homo sapiens (Human) CVCL_0594
In Vivo Model Athymic female mouse PDX model Mus musculus
Experiment for
Drug Resistance		 MTS assay
Mechanism Description MET mutations Y1248H and D1246N are resistance mechanisms for type I MET-TKIs. NIH3T3 cells expressing either mutation showed resistance to both INC280 and crizotinib but not cabozantinib, indicating the potential of sequential use of MET inhibitors may lead to a more durable response.
Key Molecule: Hepatocyte growth factor receptor (MET) [13]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Capmatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D1228N (c.3682G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model NIH3T3 cells Embryo Homo sapiens (Human) CVCL_0594
In Vivo Model Athymic female mouse PDX model Mus musculus
Experiment for
Drug Resistance		 MTS assay
Mechanism Description MET mutations Y1248H and D1246N are resistance mechanisms for type I MET-TKIs. NIH3T3 cells expressing either mutation showed resistance to both INC280 and crizotinib but not cabozantinib, indicating the potential of sequential use of MET inhibitors may lead to a more durable response.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Hepatocyte growth factor receptor (MET) [11]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Capmatinib
 Drug Info 
Molecule Alteration Missense mutation
p.Y1003F (c.3008A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
WEHI-3 cells Peripheral blood Mus musculus (Mouse) CVCL_3622
Hs746T cells Skeletal muscle Homo sapiens (Human) CVCL_0333
Gp2-293 cells Fetal kidney Homo sapiens (Human) CVCL_WI48
Experiment for
Molecule Alteration		 Direct sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Hepatocyte growth factor receptor (MET) [11]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Capmatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D1010Y (c.3028G>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
WEHI-3 cells Peripheral blood Mus musculus (Mouse) CVCL_3622
Hs746T cells Skeletal muscle Homo sapiens (Human) CVCL_0333
Gp2-293 cells Fetal kidney Homo sapiens (Human) CVCL_WI48
Experiment for
Molecule Alteration		 Direct sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Carboplatin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: TP53 target 1 (TP53TG1) [15]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Carboplatin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Y-box-binding protein 1 (YBX1) [15]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Carboplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
Cisplatin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: TP53 target 1 (TP53TG1) [15]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Y-box-binding protein 1 (YBX1) [15]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
Conivaptan
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: Heme oxygenase 1 (HMOX1) [16]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Conivaptan
 Drug Info 
Molecule Alteration Function
Inhibition
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model ATCC 293T cells Fetal kidney Homo sapiens (Human) CVCL_0063
Experiment for
Molecule Alteration		 Resazurin assay
Mechanism Description HMOX1, PRKCA, and NEIL2 contribute to anthracycline resistance within the more complex MDR phenotype, while P-glycoprotein/ABCB1 overexpression causes not only anthracycline resistance but also resistance to other anticancer drug classes. Conivaptan has the potential to be used as the dual inhibitor of HMOX1 and PRKCA, whereas bexarotene has the potential as an HMOX1 inhibitor and desloratadine as a PRKCA inhibitor.
Key Molecule: Protein kinase C alpha (PRKCA) [16]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Conivaptan
 Drug Info 
Molecule Alteration Function
Inhibition
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model ATCC 293T cells Fetal kidney Homo sapiens (Human) CVCL_0063
Experiment for
Molecule Alteration		 Resazurin assay
Mechanism Description HMOX1, PRKCA, and NEIL2 contribute to anthracycline resistance within the more complex MDR phenotype, while P-glycoprotein/ABCB1 overexpression causes not only anthracycline resistance but also resistance to other anticancer drug classes. Conivaptan has the potential to be used as the dual inhibitor of HMOX1 and PRKCA, whereas bexarotene has the potential as an HMOX1 inhibitor and desloratadine as a PRKCA inhibitor.
Dacomitinib
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) [17]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Dacomitinib
 Drug Info 
Molecule Alteration IF-insertion
p.Y764_V765insHH (c.2292_2293insCATCAT)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Key Molecule: Epidermal growth factor receptor (EGFR) [17]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Dacomitinib
 Drug Info 
Molecule Alteration Duplication
p.A767_V769 (c.2299_2307)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Key Molecule: Epidermal growth factor receptor (EGFR) [17]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Dacomitinib
 Drug Info 
Molecule Alteration Duplication
p.S768_D770 (c.2302_2310)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Dacomitinib
 Drug Info 
Molecule Alteration Duplication
p.Y772_A775 (c.2314_2325)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Drug Sensitivity 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) [17]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Complex-indel
p.D770_770delinsGY (c.2308_2310delinsGGTTAT)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Key Molecule: Epidermal growth factor receptor (EGFR) [19]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Missense mutation
p.E709K (c.2125G>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
myelomonocyti cells Bone marrow Homo sapiens (Human) N.A.
macrophage-like cells N.A. N.A. N.A.
IL3-dependent murine pro-B cells Blood Homo sapiens (Human) N.A.
Balb/C mouse leukemia cells Blood Mus musculus (Mouse) CVCL_9099
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Epidermal growth factor receptor (EGFR) [19]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Complex-indel
p.E709_T710delinsD (c.2127_2129delAAC)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
myelomonocyti cells Bone marrow Homo sapiens (Human) N.A.
macrophage-like cells N.A. N.A. N.A.
IL3-dependent murine pro-B cells Blood Homo sapiens (Human) N.A.
Balb/C mouse leukemia cells Blood Mus musculus (Mouse) CVCL_9099
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Epidermal growth factor receptor (EGFR) [19]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Missense mutation
p.G719A (c.2156G>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
myelomonocyti cells Bone marrow Homo sapiens (Human) N.A.
macrophage-like cells N.A. N.A. N.A.
IL3-dependent murine pro-B cells Blood Homo sapiens (Human) N.A.
Balb/C mouse leukemia cells Blood Mus musculus (Mouse) CVCL_9099
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [17]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Complex-indel
p.M774_774delinsWLV (c.2320_2322delinsTGGCTTGTA)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [17]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Duplication
p.G778_P780 (c.2332_2340)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [17]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration IF-insertion
p.G778_S779insCPG (c.2335_2336insGTCCTGGTT)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Complex-indel
p.G776_776delinsVC (c.2326_2328delinsGTATGT)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Duplication
p.G778_P780 (c.2332_2340)/p.780_Y781insGSP
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Daunorubicin
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [20]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Daunorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model CR1R12 cells N.A. Homo sapiens (Human) N.A.
NIH-G185 cells Ovary Homo sapiens (Human) CVCL_L991
Experiment for
Drug Resistance		 propidium iodide staining assay
Mechanism Description In a NIH-G185 cell line presenting an overexpressed amount of the human transporter P-gp, cholesterol caused dramatic inhibition of daunorubicin transport with an IC(50) of about 8 microM yet had no effect on the parent cell line nor rhodamine 123 transport.
Desloratadine
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: Protein kinase C alpha (PRKCA) [16]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Desloratadine
 Drug Info 
Molecule Alteration Function
Inhibition
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model ATCC 293T cells Fetal kidney Homo sapiens (Human) CVCL_0063
Experiment for
Molecule Alteration		 Resazurin assay
Mechanism Description HMOX1, PRKCA, and NEIL2 contribute to anthracycline resistance within the more complex MDR phenotype, while P-glycoprotein/ABCB1 overexpression causes not only anthracycline resistance but also resistance to other anticancer drug classes. Conivaptan has the potential to be used as the dual inhibitor of HMOX1 and PRKCA, whereas bexarotene has the potential as an HMOX1 inhibitor and desloratadine as a PRKCA inhibitor.
Doxorubicin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: TP53 target 1 (TP53TG1) [15]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Y-box-binding protein 1 (YBX1) [15]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-495 [21]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A2780 cells Ovary Homo sapiens (Human) CVCL_0134
A2780C cells Ovary Homo sapiens (Human) CVCL_0134
A2780DX5 cells Ovary Homo sapiens (Human) CVCL_4T98
SGC7901R cells Uterus Homo sapiens (Human) CVCL_0520
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 Annexin-V-FITC apoptosis detection assay; Caspase-3 activity assay; MTT assay; Trypan blue exclusion assay
Mechanism Description miR-495 sensitizes MDR cancer cells to the combination of doxorubicin and taxol by inhibiting MDR1 expression, miR-495 was predicted to target ABCB1, which encodes protein MDR1.
  Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [21]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A2780 cells Ovary Homo sapiens (Human) CVCL_0134
A2780C cells Ovary Homo sapiens (Human) CVCL_0134
A2780DX5 cells Ovary Homo sapiens (Human) CVCL_4T98
SGC7901R cells Uterus Homo sapiens (Human) CVCL_0520
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Annexin-V-FITC apoptosis detection assay; Caspase-3 activity assay; MTT assay; Trypan blue exclusion assay
Mechanism Description miR-495 sensitizes MDR cancer cells to the combination of doxorubicin and taxol by inhibiting MDR1 expression, miR-495 was predicted to target ABCB1, which encodes protein MDR1.
Erdafitinib
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: Fibroblast growth factor receptor 3 (FGFR3) [22]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Erdafitinib
 Drug Info 
Molecule Alteration Missense mutation
p.K650E (c.1948A>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.53  Å
PDB: 6LVM
Mutant Type Structure Method: X-ray diffraction Resolution: 2.34  Å
PDB: 4K33
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.24
TM score: 0.96738
Amino acid change:
K650E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
G
-
S
-
S
-
H
440
|
-
H
-
H
-
H
-
H
-
H
-
S
-
Q
G
D
S
P
H
P
450
|
M
T
L
L
A
A
G
N
V
V
S
S
E
E
Y
L
E
E
L
L
460
|
P
P
E
A
D
D
P
P
K
K
W
W
E
E
F
L
P
S
R
R
470
|
D
A
K
R
L
L
T
T
L
L
G
G
K
K
P
P
L
L
G
G
480
|
E
E
G
G
C
A
F
F
G
G
Q
Q
V
V
V
V
M
M
A
A
490
|
E
E
A
A
I
I
G
G
I
I
D
D
K
K
D
D
R
R
A
A
500
|
A
A
K
K
P
P
V
V
T
T
V
V
A
A
V
V
K
K
M
M
510
|
L
L
K
K
D
D
D
D
A
A
T
T
D
D
K
K
D
D
L
L
520
|
S
S
D
D
L
L
V
V
S
S
E
E
M
M
E
E
M
M
M
M
530
|
K
K
M
M
I
I
G
G
K
K
H
H
K
K
N
N
I
I
I
I
540
|
N
N
L
L
L
L
G
G
A
A
C
C
T
T
Q
Q
G
G
G
G
550
|
P
P
L
L
Y
Y
V
V
L
L
V
V
E
E
Y
Y
A
A
A
A
560
|
K
K
G
G
N
N
L
L
R
R
E
E
F
F
L
L
R
R
A
A
570
|
R
R
R
R
P
P
P
P
G
G
L
L
D
D
Y
Y
S
S
F
F
580
|
D
D
T
T
C
S
K
K
P
P
P
P
E
E
E
E
Q
Q
L
L
590
|
T
T
F
F
K
K
D
D
L
L
V
V
S
S
C
C
A
A
Y
Y
600
|
Q
Q
V
V
A
A
R
R
G
G
M
M
E
E
Y
Y
L
L
A
A
610
|
S
S
Q
Q
K
K
C
C
I
I
H
H
R
R
D
D
L
L
A
A
620
|
A
A
R
R
N
N
V
V
L
L
V
V
T
T
E
E
D
D
N
N
630
|
V
V
M
M
K
K
I
I
A
A
D
D
F
F
G
G
L
L
A
A
640
|
R
R
D
D
V
V
H
H
N
N
L
L
D
D
Y
Y
Y
Y
K
K
650
|
K
E
T
T
T
T
N
N
G
G
R
R
L
L
P
P
V
V
K
K
660
|
W
W
M
M
A
A
P
P
E
E
A
A
L
L
F
F
D
D
R
R
670
|
V
V
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
680
|
F
F
G
G
V
V
L
L
L
L
W
W
E
E
I
I
F
F
T
T
690
|
L
L
G
G
G
G
S
S
P
P
Y
Y
P
P
G
G
I
I
P
P
700
|
V
V
E
E
E
E
L
L
F
F
K
K
L
L
L
L
K
K
E
E
710
|
G
G
H
H
R
R
M
M
D
D
K
K
P
P
A
A
N
N
C
C
720
|
T
T
H
H
D
D
L
L
Y
Y
M
M
I
I
M
M
R
R
E
E
730
|
C
C
W
W
H
H
A
A
A
A
P
P
S
S
Q
Q
R
R
P
P
740
|
T
T
F
F
K
K
Q
Q
L
L
V
V
E
E
D
D
L
L
D
D
750
|
R
R
V
V
L
L
T
T
V
V
T
T
S
S
T
T
D
D
E
E
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NIH3T3 cells Embryo Homo sapiens (Human) CVCL_0594
Experiment for
Drug Resistance		 Promega assay
Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [22]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Erdafitinib
 Drug Info 
Molecule Alteration Missense mutation
p.N540K (c.1620C>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NIH3T3 cells Embryo Homo sapiens (Human) CVCL_0594
Experiment for
Drug Resistance		 Promega assay
Erlotinib
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: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Duplication
p.Y772_A775 (c.2314_2325)/p.A775_G776insYVMA
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Complex-indel
p.G776_776delinsVC (c.2326_2328delinsGTATGT)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Duplication
p.G778_P780 (c.2332_2340)/p.780_Y781insGSP
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Infigratinib
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: Fibroblast growth factor receptor 3 (FGFR3) [23]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Infigratinib
 Drug Info 
Molecule Alteration Missense mutation
p.K650E (c.1948A>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.53  Å
PDB: 6LVM
Mutant Type Structure Method: X-ray diffraction Resolution: 2.34  Å
PDB: 4K33
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.24
TM score: 0.96738
Amino acid change:
K650E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
G
-
S
-
S
-
H
440
|
-
H
-
H
-
H
-
H
-
H
-
S
-
Q
G
D
S
P
H
P
450
|
M
T
L
L
A
A
G
N
V
V
S
S
E
E
Y
L
E
E
L
L
460
|
P
P
E
A
D
D
P
P
K
K
W
W
E
E
F
L
P
S
R
R
470
|
D
A
K
R
L
L
T
T
L
L
G
G
K
K
P
P
L
L
G
G
480
|
E
E
G
G
C
A
F
F
G
G
Q
Q
V
V
V
V
M
M
A
A
490
|
E
E
A
A
I
I
G
G
I
I
D
D
K
K
D
D
R
R
A
A
500
|
A
A
K
K
P
P
V
V
T
T
V
V
A
A
V
V
K
K
M
M
510
|
L
L
K
K
D
D
D
D
A
A
T
T
D
D
K
K
D
D
L
L
520
|
S
S
D
D
L
L
V
V
S
S
E
E
M
M
E
E
M
M
M
M
530
|
K
K
M
M
I
I
G
G
K
K
H
H
K
K
N
N
I
I
I
I
540
|
N
N
L
L
L
L
G
G
A
A
C
C
T
T
Q
Q
G
G
G
G
550
|
P
P
L
L
Y
Y
V
V
L
L
V
V
E
E
Y
Y
A
A
A
A
560
|
K
K
G
G
N
N
L
L
R
R
E
E
F
F
L
L
R
R
A
A
570
|
R
R
R
R
P
P
P
P
G
G
L
L
D
D
Y
Y
S
S
F
F
580
|
D
D
T
T
C
S
K
K
P
P
P
P
E
E
E
E
Q
Q
L
L
590
|
T
T
F
F
K
K
D
D
L
L
V
V
S
S
C
C
A
A
Y
Y
600
|
Q
Q
V
V
A
A
R
R
G
G
M
M
E
E
Y
Y
L
L
A
A
610
|
S
S
Q
Q
K
K
C
C
I
I
H
H
R
R
D
D
L
L
A
A
620
|
A
A
R
R
N
N
V
V
L
L
V
V
T
T
E
E
D
D
N
N
630
|
V
V
M
M
K
K
I
I
A
A
D
D
F
F
G
G
L
L
A
A
640
|
R
R
D
D
V
V
H
H
N
N
L
L
D
D
Y
Y
Y
Y
K
K
650
|
K
E
T
T
T
T
N
N
G
G
R
R
L
L
P
P
V
V
K
K
660
|
W
W
M
M
A
A
P
P
E
E
A
A
L
L
F
F
D
D
R
R
670
|
V
V
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
680
|
F
F
G
G
V
V
L
L
L
L
W
W
E
E
I
I
F
F
T
T
690
|
L
L
G
G
G
G
S
S
P
P
Y
Y
P
P
G
G
I
I
P
P
700
|
V
V
E
E
E
E
L
L
F
F
K
K
L
L
L
L
K
K
E
E
710
|
G
G
H
H
R
R
M
M
D
D
K
K
P
P
A
A
N
N
C
C
720
|
T
T
H
H
D
D
L
L
Y
Y
M
M
I
I
M
M
R
R
E
E
730
|
C
C
W
W
H
H
A
A
A
A
P
P
S
S
Q
Q
R
R
P
P
740
|
T
T
F
F
K
K
Q
Q
L
L
V
V
E
E
D
D
L
L
D
D
750
|
R
R
V
V
L
L
T
T
V
V
T
T
S
S
T
T
D
D
E
E
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Gallbladder N.A.
Experiment for
Molecule Alteration		 Targeted sequencing of tumor tissue assay
Mechanism Description The missense mutation p.K650E (c.1948A>G) in gene FGFR3 cause the resistance of Infigratinib by aberration of the drug's therapeutic target
Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [23]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Infigratinib
 Drug Info 
Molecule Alteration Missense mutation
p.V555M (c.1663G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.53  Å
PDB: 6LVM
Mutant Type Structure Method: X-ray diffraction Resolution: 2.35  Å
PDB: 8UDV
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.03
TM score: 0.90455
Amino acid change:
V555M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
H
-
450
|
M
-
L
-
A
-
G
-
V
M
S
S
E
E
Y
L
E
E
L
L
460
|
P
P
E
A
D
D
P
P
K
K
W
W
E
E
F
L
P
S
R
R
470
|
D
A
K
R
L
L
T
T
L
L
G
G
K
K
P
P
L
L
G
G
480
|
E
E
G
G
C
C
F
F
G
G
Q
Q
V
V
V
V
M
M
A
A
490
|
E
E
A
A
I
I
G
G
I
I
D
D
K
K
D
D
R
R
A
A
500
|
A
A
K
K
P
P
V
V
T
T
V
V
A
A
V
V
K
K
M
M
510
|
L
L
K
K
D
D
D
D
A
A
T
T
D
D
K
K
D
D
L
L
520
|
S
S
D
D
L
L
V
V
S
S
E
E
M
M
E
E
M
M
M
M
530
|
K
K
M
M
I
I
G
G
K
K
H
H
K
K
N
N
I
I
I
I
540
|
N
N
L
L
L
L
G
G
A
A
C
C
T
T
Q
Q
G
G
G
G
550
|
P
P
L
L
Y
Y
V
V
L
L
V
M
E
E
Y
Y
A
A
A
A
560
|
K
K
G
G
N
N
L
L
R
R
E
E
F
F
L
L
R
R
A
A
570
|
R
R
R
R
P
S
P
G
G
-
L
-
D
-
Y
-
S
-
F
-
580
|
D
-
T
-
C
-
K
-
P
-
P
-
E
E
E
E
Q
Q
L
L
590
|
T
T
F
F
K
K
D
D
L
L
V
V
S
S
C
C
A
A
Y
Y
600
|
Q
Q
V
V
A
A
R
R
G
G
M
M
E
E
Y
Y
L
L
A
A
610
|
S
S
Q
Q
K
K
C
C
I
I
H
H
R
R
D
D
L
L
A
A
620
|
A
A
R
R
N
N
V
V
L
L
V
V
T
T
E
E
D
D
N
N
630
|
V
V
M
M
K
K
I
I
A
A
D
D
F
F
G
G
L
L
A
A
640
|
R
R
D
D
V
V
H
H
N
N
L
L
D
D
Y
Y
Y
Y
K
K
650
|
K
K
T
T
T
T
N
N
G
G
R
R
L
L
P
P
V
V
K
K
660
|
W
W
M
M
A
A
P
P
E
E
A
A
L
L
F
F
D
D
R
R
670
|
V
V
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
680
|
F
F
G
G
V
V
L
L
L
L
W
W
E
E
I
I
F
F
T
T
690
|
L
L
G
G
G
G
S
S
P
P
Y
Y
P
P
G
G
I
I
P
P
700
|
V
V
E
E
E
E
L
L
F
F
K
K
L
L
L
L
K
K
E
E
710
|
G
G
H
H
R
R
M
M
D
D
K
K
P
P
A
A
N
N
C
C
720
|
T
T
H
H
D
D
L
L
Y
Y
M
M
I
I
M
M
R
R
E
E
730
|
C
C
W
W
H
H
A
A
A
A
P
P
S
S
Q
Q
R
R
P
P
740
|
T
T
F
F
K
K
Q
Q
L
L
V
V
E
E
D
D
L
L
D
D
750
|
R
R
V
V
L
L
T
T
V
V
T
T
S
S
T
H
D
H
E
H
760
|
-
H
-
H
-
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Gallbladder N.A.
Experiment for
Molecule Alteration		 Targeted sequencing of tumor tissue assay
Mechanism Description The missense mutation p.V555M (c.1663G>A) in gene FGFR3 cause the resistance of Infigratinib by aberration of the drug's therapeutic target
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [23]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Infigratinib
 Drug Info 
Molecule Alteration Missense mutation
p.V564F (c.1690G>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.40  Å
PDB: 2PSQ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.22  Å
PDB: 7KIA
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.64
TM score: 0.98452
Amino acid change:
V564F
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
-
400
|
G
-
S
-
S
-
H
-
H
-
H
-
H
-
H
-
H
-
S
-
410
|
Q
-
D
-
P
-
P
-
A
-
V
-
H
-
K
-
L
-
T
-
420
|
K
-
R
-
I
-
P
-
L
-
R
-
R
-
Q
-
V
-
T
-
430
|
V
-
S
-
A
-
E
-
S
-
S
-
S
-
S
-
M
-
N
-
440
|
S
-
N
-
T
-
P
-
L
-
V
-
R
-
I
-
T
-
T
-
450
|
R
-
L
-
S
-
S
-
T
-
A
-
D
-
T
-
P
-
M
-
460
|
L
-
A
A
G
G
V
V
S
S
E
E
Y
Y
E
E
L
L
P
P
470
|
E
E
D
D
P
P
K
K
W
W
E
E
F
F
P
P
R
R
D
D
480
|
K
K
L
L
T
T
L
L
G
G
K
K
P
P
L
L
G
G
E
E
490
|
G
G
C
C
F
F
G
G
Q
Q
V
V
V
V
M
M
A
A
E
E
500
|
A
A
V
V
G
G
I
I
D
D
K
K
D
D
K
K
P
P
K
K
510
|
E
E
A
A
V
V
T
T
V
V
A
A
V
V
K
K
M
M
L
L
520
|
K
K
D
D
D
D
A
A
T
T
E
E
K
K
D
D
L
L
S
S
530
|
D
D
L
L
V
V
S
S
E
E
M
M
E
E
M
M
M
M
K
K
540
|
M
M
I
I
G
G
K
K
H
H
K
K
N
N
I
I
I
I
N
N
550
|
L
L
L
L
G
G
A
A
C
C
T
T
Q
Q
D
D
G
G
P
P
560
|
L
L
Y
Y
V
V
I
I
V
F
E
E
Y
Y
A
A
S
S
K
K
570
|
G
G
N
N
L
L
R
R
E
E
Y
Y
L
L
R
R
A
A
R
R
580
|
R
R
P
P
P
P
G
G
M
M
E
E
Y
Y
S
S
Y
Y
D
D
590
|
I
I
N
N
R
R
V
V
P
P
E
E
E
E
Q
Q
M
M
T
T
600
|
F
F
K
K
D
D
L
L
V
V
S
S
C
C
T
T
Y
Y
Q
Q
610
|
L
L
A
A
R
R
G
G
M
M
E
E
Y
Y
L
L
A
A
S
S
620
|
Q
Q
K
K
C
C
I
I
H
H
R
R
D
D
L
L
A
A
A
A
630
|
R
R
N
N
V
V
L
L
V
V
T
T
E
E
N
N
N
N
V
V
640
|
M
M
K
K
I
I
A
A
D
D
F
F
G
G
L
L
A
A
R
R
650
|
D
D
I
I
N
N
N
N
I
I
D
D
Y
Y
Y
Y
K
K
K
K
660
|
T
T
T
T
N
N
G
G
R
R
L
L
P
P
V
V
K
K
W
W
670
|
M
M
A
A
P
P
E
E
A
A
L
L
F
F
D
D
R
R
V
V
680
|
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
690
|
G
G
V
V
L
L
M
M
W
W
E
E
I
I
F
F
T
T
L
L
700
|
G
G
G
G
S
S
P
P
Y
Y
P
P
G
G
I
I
P
P
V
V
710
|
E
E
E
E
L
L
F
F
K
K
L
L
L
L
K
K
E
E
G
G
720
|
H
H
R
R
M
M
D
D
K
K
P
P
A
A
N
N
C
C
T
T
730
|
N
N
E
E
L
L
Y
Y
M
M
M
M
M
M
R
R
D
D
C
C
740
|
W
W
H
H
A
A
V
V
P
P
S
S
Q
Q
R
R
P
P
T
T
750
|
F
F
K
K
Q
Q
L
L
V
V
E
E
D
D
L
L
D
D
R
R
760
|
I
I
L
L
T
T
L
L
T
T
T
T
N
N
E
E
E
E
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Gallbladder N.A.
Experiment for
Molecule Alteration		 Targeted sequencing of tumor tissue assay
Mechanism Description The missense mutation p.V564F (c.1690G>T) in gene FGFR2 cause the resistance of Infigratinib by aberration of the drug's therapeutic target
Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [23]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Infigratinib
 Drug Info 
Molecule Alteration Missense mutation
p.N540K (c.1620C>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Gallbladder N.A.
Experiment for
Molecule Alteration		 Targeted sequencing of tumor tissue assay
Mechanism Description The missense mutation p.N540K (c.1620C>G) in gene FGFR3 cause the resistance of Infigratinib by aberration of the drug's therapeutic target
Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [23]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Infigratinib
 Drug Info 
Molecule Alteration Missense mutation
p.V555L (c.1663G>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Gallbladder N.A.
Experiment for
Molecule Alteration		 Targeted sequencing of tumor tissue assay
Mechanism Description The missense mutation p.V555L (c.1663G>C) in gene FGFR3 cause the resistance of Infigratinib by aberration of the drug's therapeutic target
Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [23]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Infigratinib
 Drug Info 
Molecule Alteration Missense mutation
p.L608V (c.1822T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Gallbladder N.A.
Experiment for
Molecule Alteration		 Targeted sequencing of tumor tissue assay
Mechanism Description The missense mutation p.L608V (c.1822T>G) in gene FGFR3 cause the resistance of Infigratinib by aberration of the drug's therapeutic target
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [24]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Infigratinib
 Drug Info 
Molecule Alteration Missense mutation
p.K660E (c.1978A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Soft-agar colony formation assay
Mechanism Description The missense mutation p.K660E (c.1978A>G) in gene FGFR2 cause the sensitivity of Infigratinib by aberration of the drug's therapeutic target
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [24]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Infigratinib
 Drug Info 
Molecule Alteration Missense mutation
p.K660N (c.1980G>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Soft-agar colony formation assay
Mechanism Description The missense mutation p.K660N (c.1980G>C) in gene FGFR2 cause the sensitivity of Infigratinib by aberration of the drug's therapeutic target
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [24]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Infigratinib
 Drug Info 
Molecule Alteration Missense mutation
p.W290C (c.870G>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Soft-agar colony formation assay
Mechanism Description The missense mutation p.W290C (c.870G>T) in gene FGFR2 cause the sensitivity of Infigratinib by aberration of the drug's therapeutic target
Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [24]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Infigratinib
 Drug Info 
Molecule Alteration Missense mutation
p.R248C (c.742C>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Soft-agar colony formation assay
Mechanism Description The missense mutation p.R248C (c.742C>T) in gene FGFR3 cause the sensitivity of Infigratinib by aberration of the drug's therapeutic target
Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [24]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Infigratinib
 Drug Info 
Molecule Alteration Missense mutation
p.S249C (c.746C>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Soft-agar colony formation assay
Mechanism Description The missense mutation p.S249C (c.746C>G) in gene FGFR3 cause the sensitivity of Infigratinib by aberration of the drug's therapeutic target
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [25]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Infigratinib
 Drug Info 
Molecule Alteration Duplication
p.S267_D273 (c.799_819)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
In Vivo Model Nu/Nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Soft-agar colony formation assay
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [25]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Infigratinib
 Drug Info 
Molecule Alteration Complex-indel
p.W290_I291delinsC (c.870_872delGAT)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
In Vivo Model Nu/Nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Soft-agar colony formation assay
Irinotecan
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: TP53 target 1 (TP53TG1) [15]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Irinotecan
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Y-box-binding protein 1 (YBX1) [15]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Irinotecan
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
Lapatinib
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: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Duplication
p.Y772_A775 (c.2314_2325)/p.A775_G776insYVMA
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Complex-indel
p.G776_776delinsVC (c.2326_2328delinsGTATGT)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Duplication
p.G778_P780 (c.2332_2340)/p.780_Y781insGSP
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 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) [26]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
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
Key Molecule: NT-3 growth factor receptor (TrkC) [26]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Larotrectinib
 Drug Info 
Molecule Alteration Missense mutation
p.G623R (c.1867G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: NT-3 growth factor receptor (TrkC) [27]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Larotrectinib
 Drug Info 
Molecule Alteration Other
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Lenvatinib
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: Fibroblast growth factor receptor 2 (FGFR2) [24]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Lenvatinib
 Drug Info 
Molecule Alteration Missense mutation
p.K660E (c.1978A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Soft-agar colony formation assay
Mechanism Description The missense mutation p.K660E (c.1978A>G) in gene FGFR2 cause the sensitivity of Lenvatinib by aberration of the drug's therapeutic target
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [24]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Lenvatinib
 Drug Info 
Molecule Alteration Missense mutation
p.K660N (c.1980G>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Soft-agar colony formation assay
Mechanism Description The missense mutation p.K660N (c.1980G>C) in gene FGFR2 cause the sensitivity of Lenvatinib by aberration of the drug's therapeutic target
Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [24]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Lenvatinib
 Drug Info 
Molecule Alteration Missense mutation
p.W290C (c.870G>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Soft-agar colony formation assay
Mechanism Description The missense mutation p.W290C (c.870G>T) in gene FGFR2 cause the sensitivity of Lenvatinib by aberration of the drug's therapeutic target
Midostaurin
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: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [28]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.S451F (c.1352C>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.S451F (c.1352C>T) in gene FLT3 cause the resistance of Midostaurin by unusual activation of pro-survival pathway
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [29]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration IF-deletion
p.I836delI (c.2508_2510delCAT)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Immunoblotting analysis
Mechanism Description The if-deletion p.I836delI (c.2508_2510delCAT) in gene FLT3 cause the sensitivity of Midostaurin by aberration of the drug's therapeutic target.
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [30]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.D842V (c.2525A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) CVCL_0291
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [28]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.Y572C (c.1715A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.Y572C (c.1715A>G) in gene FLT3 cause the sensitivity of Midostaurin by unusual activation of pro-survival pathway
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [28]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.V592G (c.1775T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.V592G (c.1775T>G) in gene FLT3 cause the sensitivity of Midostaurin by unusual activation of pro-survival pathway
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [28]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.R834Q (c.2501G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description The missense mutation p.R834Q (c.2501G>A) in gene FLT3 cause the sensitivity of Midostaurin by unusual activation of pro-survival pathway
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
M230 cells Skin Homo sapiens (Human) CVCL_D749
Experiment for
Molecule Alteration		 PCR
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Mitoxantrone
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [31]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Mitoxantrone
 Drug Info 
Molecule Alteration Missense mutation
p.C592A
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cytotoxicity assay
Mechanism Description Cys-603 alone displayed mitoxantrone resistance close (although not identical) to the wt (-70%), whereas both Cys-608 alone and Cys-592 alone displayed an almost identical low resistance of -10 and 5% of the wt, respectively. For both C603A/C608A and C592A/C603A, we observed a marked decrease in resistance to mitoxantrone and a concomitant decrease in expr.
Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [31]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Mitoxantrone
 Drug Info 
Molecule Alteration Missense mutation
p.C592A+p.C603A
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cytotoxicity assay
Mechanism Description Cys-603 alone displayed mitoxantrone resistance close (although not identical) to the wt (-70%), whereas both Cys-608 alone and Cys-592 alone displayed an almost identical low resistance of -10 and 5% of the wt, respectively. For both C603A/C608A and C592A/C603A, we observed a marked decrease in resistance to mitoxantrone and a concomitant decrease in expr.
Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [31]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Mitoxantrone
 Drug Info 
Molecule Alteration Missense mutation
p.C603A+p.C608A
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cytotoxicity assay
Mechanism Description Cys-603 alone displayed mitoxantrone resistance close (although not identical) to the wt (-70%), whereas both Cys-608 alone and Cys-592 alone displayed an almost identical low resistance of -10 and 5% of the wt, respectively. For both C603A/C608A and C592A/C603A, we observed a marked decrease in resistance to mitoxantrone and a concomitant decrease in expr.
Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [31]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Mitoxantrone
 Drug Info 
Molecule Alteration Missense mutation
p.C608A
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cytotoxicity assay
Mechanism Description Cys-603 alone displayed mitoxantrone resistance close (although not identical) to the wt (-70%), whereas both Cys-608 alone and Cys-592 alone displayed an almost identical low resistance of -10 and 5% of the wt, respectively. For both C603A/C608A and C592A/C603A, we observed a marked decrease in resistance to mitoxantrone and a concomitant decrease in expr.
Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [32]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Mitoxantrone
 Drug Info 
Molecule Alteration Missense mutation
p.K86M
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Colorimetric cytotoxicity assy assay
Mechanism Description Cells expressing ABCG2-wt or ABCG2-wt-MYC showed increased resistance to mitoxantrone as reflected in a sevenfold increase in IC50 value as compared to that observed for non-transfected cells (0.36 uM and 0.29 uM, for ABCG2-wt or ABCG2-wt-MYC expressing cells compared to 0.05 uM in non-transfected cells). ABCG2-k86M and ABCG2-k86M-HA displayed sensitivity comparable to that of non-transfected cells consistent with loss of function with IC50 values for mitoxantrone of 0.047 uM and and 0.043 uM
Neratinib
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: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Neratinib
 Drug Info 
Molecule Alteration Duplication
p.G778_P780 (c.2332_2340)/p.780_Y781insGSP
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Neratinib
 Drug Info 
Molecule Alteration Duplication
p.Y772_A775 (c.2314_2325)/p.A775_G776insYVMA
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Neratinib
 Drug Info 
Molecule Alteration Complex-indel
p.G776_776delinsVC (c.2326_2328delinsGTATGT)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Osimertinib
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: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Osimertinib
 Drug Info 
Molecule Alteration Duplication
p.Y772_A775 (c.2314_2325)/p.A775_G776insYVMA
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Osimertinib
 Drug Info 
Molecule Alteration Duplication
p.G778_P780 (c.2332_2340)/p.780_Y781insGSP
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [18]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Osimertinib
 Drug Info 
Molecule Alteration Complex-indel
p.G776_776delinsVC (c.2326_2328delinsGTATGT)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Oxaliplatin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: TP53 target 1 (TP53TG1) [15]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Oxaliplatin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Y-box-binding protein 1 (YBX1) [15]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Oxaliplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
Paclitaxel
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: hsa-mir-495 [21]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Paclitaxel
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A2780 cells Ovary Homo sapiens (Human) CVCL_0134
A2780C cells Ovary Homo sapiens (Human) CVCL_0134
A2780DX5 cells Ovary Homo sapiens (Human) CVCL_4T98
SGC7901R cells Uterus Homo sapiens (Human) CVCL_0520
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 Annexin-V-FITC apoptosis detection assay; Caspase-3 activity assay; MTT assay; Trypan blue exclusion assay
Mechanism Description miR-495 sensitizes MDR cancer cells to the combination of doxorubicin and taxol by inhibiting MDR1 expression, miR-495 was predicted to target ABCB1, which encodes protein MDR1.
  Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [21]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Paclitaxel
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A2780 cells Ovary Homo sapiens (Human) CVCL_0134
A2780C cells Ovary Homo sapiens (Human) CVCL_0134
A2780DX5 cells Ovary Homo sapiens (Human) CVCL_4T98
SGC7901R cells Uterus Homo sapiens (Human) CVCL_0520
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Annexin-V-FITC apoptosis detection assay; Caspase-3 activity assay; MTT assay; Trypan blue exclusion assay
Mechanism Description miR-495 sensitizes MDR cancer cells to the combination of doxorubicin and taxol by inhibiting MDR1 expression, miR-495 was predicted to target ABCB1, which encodes protein MDR1.
Pexidartinib
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: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Pexidartinib
 Drug Info 
Molecule Alteration Missense mutation
p.D835Y (c.2503G>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
In Vivo Model (Nu/Nu) male MV4; 11 xenograft mouse model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay; ATPlite 1step luminescence assay
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [33]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Pexidartinib
 Drug Info 
Molecule Alteration Missense mutation
p.D835V (c.2504A>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
In Vivo Model (Nu/Nu) male MV4; 11 xenograft mouse model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay; ATPlite 1step luminescence assay
Regorafenib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [30]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) CVCL_0291
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [34]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.P551_E554delPMYE (c.1651_1662del12)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells Gastric Homo sapiens (Human) CVCL_4976
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [34]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.D816H (c.2446G>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells Gastric Homo sapiens (Human) CVCL_4976
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [30]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.D842V (c.2525A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) CVCL_0291
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 1 (MEK1) [35]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Regorafenib
 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
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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
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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
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M
-
A
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I
-
F
-
E
-
L
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L
-
D
-
Y
-
I
280
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-
V
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N
-
E
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P
-
P
-
P
-
K
-
L
-
P
-
S
290
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G
-
V
-
F
-
S
-
L
-
E
-
F
-
Q
-
D
-
F
300
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-
V
-
N
G
K
S
C
G
L
S
I
G
K
S
N
M
P
A
A
310
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I
E
F
R
E
A
L
D
L
L
D
K
Y
Q
I
L
V
M
N
V
320
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E
H
P
A
P
F
P
I
K
K
L
R
P
S
S
D
G
A
V
E
330
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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
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F
H
I
H
K
H
R
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S
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D
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A
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E
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E
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V
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370
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D
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F
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A
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G
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W
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L
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C
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S
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T
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I
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380
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G
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L
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N
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Q
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [35]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.F53L (c.157T>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.F53L (c.157T>C) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [35]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.Q56P (c.167A>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.Q56P (c.167A>C) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [35]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.K57N (c.171G>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.K57N (c.171G>C) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [35]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.I111S (c.332T>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.I111S (c.332T>G) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [35]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.F129L (c.385T>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.F129L (c.385T>C) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [35]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V211D (c.632T>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.V211D (c.632T>A) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [34]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.P551_K558delPMYEVQWK (c.1650_1673del24)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells Gastric Homo sapiens (Human) CVCL_4976
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [34]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.W557_K558delWK (c.1669_1674delTGGAAG)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells Gastric Homo sapiens (Human) CVCL_4976
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [34]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Complex-indel
p.K558_558delinsNP (c.1672_1674delinsAACCCT)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells Gastric Homo sapiens (Human) CVCL_4976
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [34]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V560D (c.1679T>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells Gastric Homo sapiens (Human) CVCL_4976
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Ripretinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [30]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Ripretinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) CVCL_0291
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [30]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Ripretinib
 Drug Info 
Molecule Alteration Missense mutation
p.D842V (c.2525A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) CVCL_0291
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Rucaparib
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: Oxalosuccinate decarboxylase (IDH1) [36]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Rucaparib
 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 Identified from the Human Clinical Data
In Vitro Model IDH2 cells Ovary Homo sapiens (Human) CVCL_D3DY
IDH1 cells Ovary Homo sapiens (Human) CVCL_D3DY
In Vivo Model Female athymic nu/nu mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.
Ruxolitinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [37]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Ruxolitinib
 Drug Info 
Molecule Alteration Missense mutation
p.L857P (c.2570T>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
U4C cells Acetabulum Homo sapiens (Human) CVCL_D314
In Vivo Model Balb/c bone marrow transplantation mouse model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Proliferation assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [37]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Ruxolitinib
 Drug Info 
Molecule Alteration Missense mutation
p.V674A (c.2021T>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
U4C cells Acetabulum Homo sapiens (Human) CVCL_D314
In Vivo Model Balb/c bone marrow transplantation mouse model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Proliferation assay
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Granulocyte colony-stimulating factor receptor (CSF3R) [38]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Ruxolitinib
 Drug Info 
Molecule Alteration Missense mutation
p.N610H (c.1828A>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model C57/BL6 mouse model Mus musculus
Experiment for
Molecule Alteration		 Sanger genomic DNA sequencing assay
Experiment for
Drug Resistance		 MTS assay
Key Molecule: Granulocyte colony-stimulating factor receptor (CSF3R) [39]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Ruxolitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T640N (c.1919C>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T17 cells Kidney Homo sapiens (Human) CVCL_0063
In Vivo Model Balb/c bone marrow transplantation mouse model Mus musculus
Experiment for
Molecule Alteration		 Sanger sequencing assay; Western blot analysis
Experiment for
Drug Resistance		 Cytokine-independent growth assay
Key Molecule: Granulocyte colony-stimulating factor receptor (CSF3R) [38]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Ruxolitinib
 Drug Info 
Molecule Alteration Missense mutation
p.N610S (c.1829A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model C57/BL6 mouse model Mus musculus
Experiment for
Molecule Alteration		 Sanger genomic DNA sequencing assay
Experiment for
Drug Resistance		 MTS assay
Selpercatinib
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [40]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Selpercatinib
 Drug Info 
Molecule Alteration Missense mutation
p.M918T (c.2753T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
|
G
G
P
P
L
L
S
S
L
L
S
S
V
V
D
D
A
A
F
F
710
|
K
K
I
I
L
L
E
E
D
D
P
P
K
K
W
W
E
E
F
F
720
|
P
P
R
R
K
K
N
N
L
L
V
V
L
L
G
G
K
K
T
T
730
|
L
L
G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
V
740
|
K
K
A
A
T
T
A
A
F
F
H
H
L
L
K
K
G
G
R
R
750
|
A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
K
M
M
760
|
L
L
K
K
E
E
N
N
A
A
S
S
P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
V
L
L
780
|
K
K
Q
Q
V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
K
790
|
L
L
Y
Y
G
G
A
A
C
C
S
S
Q
Q
D
D
G
G
P
P
800
|
L
L
L
L
L
L
I
I
V
V
E
E
Y
Y
A
A
K
K
Y
Y
810
|
G
G
S
S
L
L
R
R
G
G
F
F
L
L
R
R
E
E
S
S
820
|
R
R
K
K
V
V
G
G
P
P
G
G
Y
Y
L
L
G
G
S
S
830
|
G
G
G
G
S
S
R
R
N
N
S
S
S
S
S
S
L
L
D
D
840
|
H
H
P
P
D
D
E
E
R
R
A
A
L
L
T
T
M
M
G
G
850
|
D
D
L
L
I
I
S
S
F
F
A
A
W
W
Q
Q
I
I
S
S
860
|
Q
Q
G
G
M
M
Q
Q
Y
Y
L
L
A
A
E
E
M
M
K
K
870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
|
I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
K
W
W
M
T
A
A
920
|
I
I
E
E
S
S
L
L
F
F
D
D
H
H
I
I
Y
Y
T
T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
|
L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
In Vivo Model Mouse PDX model Mus musculus
Mechanism Description LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations.
Sonidegib
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: Smoothened homolog (SMO) [41]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Sonidegib
 Drug Info 
Molecule Alteration Missense mutation
p.I408V (c.1222A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Carcinoma tissue basal cell N.A. Homo sapiens (Human) N.A.
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 SNP and CGH array assay
Mechanism Description The missense mutation p.I408V (c.1222A>G) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target
Key Molecule: Smoothened homolog (SMO) [41]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Sonidegib
 Drug Info 
Molecule Alteration Missense mutation
p.A459V (c.1376C>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Carcinoma tissue basal cell N.A. Homo sapiens (Human) N.A.
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 SNP and CGH array assay
Mechanism Description The missense mutation p.A459V (c.1376C>T) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target
Key Molecule: Smoothened homolog (SMO) [41]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Sonidegib
 Drug Info 
Molecule Alteration Missense mutation
p.C469Y (c.1406G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Carcinoma tissue basal cell N.A. Homo sapiens (Human) N.A.
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 SNP and CGH array assay
Mechanism Description The missense mutation p.C469Y (c.1406G>A) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target
Key Molecule: Smoothened homolog (SMO) [41]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Sonidegib
 Drug Info 
Molecule Alteration Missense mutation
p.T241M (c.722C>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Carcinoma tissue basal cell N.A. Homo sapiens (Human) N.A.
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 SNP and CGH array assay
Mechanism Description The missense mutation p.T241M (c.722C>T) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target
Key Molecule: Smoothened homolog (SMO) [41]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Sonidegib
 Drug Info 
Molecule Alteration Missense mutation
p.W281C (c.843G>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Carcinoma tissue basal cell N.A. Homo sapiens (Human) N.A.
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 SNP and CGH array assay
Mechanism Description The missense mutation p.W281C (c.843G>T) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target
Key Molecule: Smoothened homolog (SMO) [41]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Sonidegib
 Drug Info 
Molecule Alteration Missense mutation
p.V321M (c.961G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Carcinoma tissue basal cell N.A. Homo sapiens (Human) N.A.
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 SNP and CGH array assay
Mechanism Description The missense mutation p.V321M (c.961G>A) in gene SMO cause the resistance of Sonidegib by aberration of the drug's therapeutic target
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Smoothened homolog (SMO) [42]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Sonidegib
 Drug Info 
Molecule Alteration Missense mutation
p.D384N (c.1150G>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Hippo signaling pathway Inhibition hsa04390
In Vitro Model NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
HEK293S cells Fetal kidney Homo sapiens (Human) CVCL_A784
In Vivo Model NOD/SCID mouse Mus musculus
Experiment for
Molecule Alteration		 Immunofluorescence imaging assay
Experiment for
Drug Resistance		 FACS assay
Mechanism Description Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.
Key Molecule: Smoothened homolog (SMO) [42]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Sonidegib
 Drug Info 
Molecule Alteration Missense mutation
p.S387N (c.1160G>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Hippo signaling pathway Inhibition hsa04390
In Vitro Model NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
HEK293S cells Fetal kidney Homo sapiens (Human) CVCL_A784
In Vivo Model NOD/SCID mouse Mus musculus
Experiment for
Molecule Alteration		 Immunofluorescence imaging assay
Experiment for
Drug Resistance		 FACS assay
Mechanism Description Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.
Key Molecule: Smoothened homolog (SMO) [42]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Sonidegib
 Drug Info 
Molecule Alteration Missense mutation
p.E518K (c.1552G>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Hippo signaling pathway Inhibition hsa04390
In Vitro Model NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
HEK293S cells Fetal kidney Homo sapiens (Human) CVCL_A784
In Vivo Model NOD/SCID mouse Mus musculus
Experiment for
Molecule Alteration		 Immunofluorescence imaging assay
Experiment for
Drug Resistance		 FACS assay
Mechanism Description Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.
Key Molecule: Smoothened homolog (SMO) [42]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Sonidegib
 Drug Info 
Molecule Alteration Missense mutation
p.N219D (c.655A>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Hippo signaling pathway Inhibition hsa04390
In Vitro Model NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
HEK293S cells Fetal kidney Homo sapiens (Human) CVCL_A784
In Vivo Model NOD/SCID mouse Mus musculus
Experiment for
Molecule Alteration		 Immunofluorescence imaging assay
Experiment for
Drug Resistance		 FACS assay
Mechanism Description Posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo.
Tazemetostat
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: Histone-lysine N-methyltransferase EZH2 (EZH2) [43]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Resistant Drug Tazemetostat
 Drug Info 
Molecule Alteration Missense mutation
p.Y111D (c.331T>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Pfeiffer cells Pleural effusion Homo sapiens (Human) CVCL_3326
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
Tegafur
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Dihydropyrimidine dehydrogenase [NADP(+)] [44]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Sensitive Drug Tegafur
 Drug Info 
Molecule Alteration Missense mutation
p.I560S (c.1679T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
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