Drug Information

Drug (ID: DG00050) and It's Reported Resistant Information
Name
Crizotinib
Synonyms
Xalkori (TN); novel ALK inhibitors
    Click to Show/Hide
Indication
In total 1 Indication(s)
Lung cancer [ICD-11: 2C25]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Brain cancer [ICD-11: 2A00]
[2]
Lung cancer [ICD-11: 2C25]
[3], [4], [5]
Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
Lung cancer [ICD-11: 2C25]
[6]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Lung cancer [ICD-11: 2C25]
[1]
Target ALK tyrosine kinase receptor (ALK) ALK_HUMAN [1]
HGF/Met signaling pathway (HGF/Met pathway) NOUNIPROTAC [1]
Proto-oncogene c-Met (MET) MET_HUMAN [1]
Proto-oncogene c-Ros (ROS1) ROS1_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C21H22Cl2FN5O
IsoSMILES
C[C@H](C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N
InChI
1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1
InChIKey
KTEIFNKAUNYNJU-GFCCVEGCSA-N
PubChem CID
11626560
ChEBI ID
CHEBI:64310
TTD Drug ID
D03ZBT
VARIDT ID
DR00523
INTEDE ID
DR0387
DrugBank ID
DB08865
Type(s) of Resistant Mechanism of This Drug due to Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  EADR: Epigenetic Alteration of DNA, RNA or Protein
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Brain cancer [ICD-11: 2A00]
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 Neuroblastoma [ICD-11: 2A00.11]
 Disease Info 
Molecule Alteration Missense mutation
p.F1174L
 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
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G
-
M
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1070
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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
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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
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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
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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
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P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
G
1270
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D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
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A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
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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
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T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
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W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
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Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
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E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
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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 Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
In Vitro Model NBLW cells Brain Homo sapiens (Human) CVCL_VJ90
NBLW-R cells Brain Homo sapiens (Human) CVCL_VJ91
Experiment for
Molecule Alteration		 Sangersequencing assay; Targeted deep sequencing assay
Experiment for
Drug Resistance		 Array CGH assay
Mechanism Description Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALk inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALk inhibitor induced apoptosis compared with NBLW cells.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [2]
Resistant Disease Neuroblastoma [ICD-11: 2A00.11]
 Disease Info 
Molecule Alteration Missense mutation
p.F1174L
 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
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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
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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
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I
I
I
I
S
S
K
K
F
L
N
N
H
H
Q
Q
N
N
I
I
1180
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V
V
R
R
C
C
I
I
G
G
V
V
S
S
L
L
Q
Q
S
S
1190
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L
L
P
P
R
R
F
F
I
I
L
L
L
L
E
E
L
L
M
M
1200
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A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
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E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
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S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
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A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
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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
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D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
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A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
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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
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T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
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W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
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Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
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E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
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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
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P
P
E
E
D
D
R
R
P
P
N
N
F
F
A
A
I
I
I
I
1380
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L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
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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
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K
K
V
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ALK signaling pathway Activation hsa05200
Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
In Vitro Model NCI-H3122 cells Lung Homo sapiens (Human) CVCL_5160
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay
Experiment for
Drug Resistance		 MTS assay
Mechanism Description There is a C to G mutation (asterix) in codon 3522 in exon 23 resulting in the F1174L mutation. When present in cis with an ALk translocation, this mutation (also detected in neuroblastomas) causes an increase in ALk phosphorylation, cell growth and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib mediated downregulation of ALk signaling and blocks apoptosis in RANBP2-ALk Ba/F3 cells.
Lung cancer [ICD-11: 2C25]
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) [4], [8], [9]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.G1269A
 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
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1070
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M
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A
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H
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H
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H
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H
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H
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H
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D
-
Y
1080
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-
G
-
I
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P
-
T
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T
-
E
-
N
-
L
-
Y
-
F
1090
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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
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E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
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R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
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V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
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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
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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 Identified from the Human Clinical Data
Cell Pathway Regulation JAKT/STAT signaling pathway Activation hsa04630
In Vitro Model ALCL cells Lung Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Low throughout experiment assay; Pyrosequencing analysis; Droplet digital PCR assay; Next generation deep sequencing assay; Next-generation sequencing assay; Low throughput experiment assay
Experiment for
Drug Resistance		 X-ray tomography assay; Analysis of progression-free survival (PFS) assay; Computerized tomography assay; Progression-free survival assay
Mechanism Description The L1196M gatekeeper mutation is the most common ALk mutation conferring crizotinib resistance while other resistance mutations include I1171T, F1174C, G1202R, S1206Y, and G1269A. The drugs bind to an inactive enzyme and they do not extend past the gatekeeper into the back pocket of the drug binding site. By applying a base-pair specific error-weighted mutation calling algorithm (BASCA) that we developed for this assay, genomic DNA analysis from thirteen relapsed patients revealed three known crizotinib resistance mutations, C1156Y, L1196M and G1269A. Our assay demonstrates robust and sensitive detection of ALk kinase mutations in NSCLC tumor samples and aids in the elucidation of resistance mechanisms pertinent to the clinical setting. Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALk) gene rearrangements invariably develop resistance to the ALk tyrosine kinase inhibitor (TkI) crizotinib. In particular, ceritinib effectively inhibits ALk harboring L1196M, G1269A, I1171T and S1206Y mutations, and a co-crystal of ceritinib bound to ALk provides structural bases for this increased potency. Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure.
Key Molecule: ALK tyrosine kinase receptor (ALK) [10], [11]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.G1269A
 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 Identified from the Human Clinical Data
In Vitro Model NCI-H2228 cells Lung Homo sapiens (Human) CVCL_1543
NCI-H3122 cells Lung Homo sapiens (Human) CVCL_5160
SNU-2535 cells Lung Homo sapiens (Human) CVCL_R756
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay; Digital droplet PCR assay; Sanger sequencing assay
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay; Progression-free survival (PFS) assay
Mechanism Description Three patients harbored secondary ALk mutations, including one patient with both mutations: L1196M (n = 2) and G1269A (n = 2). Genetic changes associated with crizotinib resistance are heterogeneous in ALk-rearranged NSCLC patients who respond to crizotinib and subsequently develop resistance. ALk-dependent mechanisms include gatekeeper (L1196M) or other mutations such as C1156Y and G1269A in the ALk kinase domain and ALk copy number gain.
Key Molecule: ALK tyrosine kinase receptor (ALK) [12]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.L1196M
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.66  Å
PDB: 4CLJ
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.69
TM score: 0.97734
Amino acid change:
L1196M
 : 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
-
T
M
S
A
T
H
I
H
M
H
1090
|
T
H
D
H
Y
H
N
N
P
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
M
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
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation JAKT/STAT signaling pathway Activation hsa04630
In Vitro Model ALCL cells Lung Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Low throughout experiment assay
Experiment for
Drug Resistance		 X-ray tomography assay
Mechanism Description The L1196M gatekeeper mutation is the most common ALk mutation conferring crizotinib resistance while other resistance mutations include I1171T, F1174C, G1202R, S1206Y, and G1269A. The drugs bind to an inactive enzyme and they do not extend past the gatekeeper into the back pocket of the drug binding site. By applying a base-pair specific error-weighted mutation calling algorithm (BASCA) that we developed for this assay, genomic DNA analysis from thirteen relapsed patients revealed three known crizotinib resistance mutations, C1156Y, L1196M and G1269A. Our assay demonstrates robust and sensitive detection of ALk kinase mutations in NSCLC tumor samples and aids in the elucidation of resistance mechanisms pertinent to the clinical setting. Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure. In contrast, cells expressing either the C1156Y or L1196M mutant form manifested a markedly reduced sensitivity to the drug.
Key Molecule: ALK tyrosine kinase receptor (ALK) [13], [10]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L1196M
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.66  Å
PDB: 4CLJ
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.69
TM score: 0.97734
Amino acid change:
L1196M
 : 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
-
T
M
S
A
T
H
I
H
M
H
1090
|
T
H
D
H
Y
H
N
N
P
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
M
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
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1230
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A
A
R
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I
I
A
A
C
C
G
G
C
C
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Y
1240
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L
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E
E
E
E
N
N
H
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F
F
I
I
H
H
R
R
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D
1250
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I
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A
A
A
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N
N
C
C
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C
C
1260
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G
1270
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F
F
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M
M
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A
R
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I
Y
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1280
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A
A
S
S
Y
Y
Y
Y
R
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K
K
G
G
G
G
C
C
A
A
1290
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M
L
L
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P
V
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K
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W
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P
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E
1300
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E
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K
1310
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1320
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G
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1330
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Y
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E
V
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L
1340
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E
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F
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T
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S
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G
G
G
G
R
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M
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D
1350
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P
P
P
P
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K
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C
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Y
1360
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A
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1380
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E
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1390
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N
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T
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A
A
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P
P
I
I
1400
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E
E
Y
Y
G
G
P
P
L
L
V
V
E
E
E
E
E
E
E
E
1410
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K
K
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model NCI-H2228 cells Lung Homo sapiens (Human) CVCL_1543
NCI-H3122 cells Lung Homo sapiens (Human) CVCL_5160
SNU-2535 cells Lung Homo sapiens (Human) CVCL_R756
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay; Sanger dideoxynucleotide sequencing assay
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay; CellTiter-Glo assay
Mechanism Description Three patients harbored secondary ALk mutations, including one patient with both mutations: L1196M (n = 2) and G1269A (n = 2). Genetic changes associated with crizotinib resistance are heterogeneous in ALk-rearranged NSCLC patients who respond to crizotinib and subsequently develop resistance. In 1 of the 15 cases examined, ALk FISH revealed high-level gene amplification. No ALk resistance mutations were found in this specimen, so it appears that high-level amplification of the wild-type ALk fusion gene is sufficient to cause resistance.
Key Molecule: ALK tyrosine kinase receptor (ALK) [11]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.C1156Y
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.60  Å
PDB: 5A9U
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.78
TM score: 0.9838
Amino acid change:
C1156Y
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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G
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M
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1070
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Q
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M
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E
-
L
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S
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1080
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L
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S
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K
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L
-
R
-
T
M
S
A
T
H
I
H
M
H
1090
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T
H
D
H
Y
H
N
N
P
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
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E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
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R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
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V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
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N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
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K
K
T
T
L
L
P
P
E
E
V
V
C
Y
S
S
E
E
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Q
1160
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D
D
E
E
L
L
D
D
F
F
L
L
M
M
E
E
A
A
L
L
1170
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I
I
I
I
S
S
K
K
F
F
N
N
H
H
Q
Q
N
N
I
I
1180
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V
V
R
R
C
C
I
I
G
G
V
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S
1190
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L
L
P
P
R
R
F
F
I
I
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L
L
L
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E
L
L
M
M
1200
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A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
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E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
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S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
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A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
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Q
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Y
1240
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L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
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I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
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P
P
G
G
P
P
G
G
R
R
V
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A
A
K
K
I
I
G
G
1270
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D
D
F
F
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G
M
M
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A
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D
I
I
Y
Y
R
R
1280
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A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
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M
M
L
L
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P
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K
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M
M
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E
1300
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E
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S
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K
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T
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L
1320
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E
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M
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P
1330
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Y
Y
P
P
S
S
K
K
S
S
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N
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Q
E
E
V
V
L
L
1340
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E
E
F
F
V
V
T
T
S
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G
G
G
G
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D
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Y
1360
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F
A
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I
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I
1380
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L
L
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E
R
R
I
I
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Y
C
C
T
T
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Q
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D
1390
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D
D
V
V
I
I
N
N
T
T
A
A
L
L
P
P
I
I
1400
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E
E
Y
Y
G
G
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P
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V
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E
E
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E
1410
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V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Digital droplet PCR assay; Sanger sequencing assay
Experiment for
Drug Resistance		 Analysis of progression-free survival (PFS) assay
Mechanism Description ALk-dependent mechanisms include gatekeeper (L1196M) or other mutations such as C1156Y and G1269A in the ALk kinase domain and ALk copy number gain.
Key Molecule: ALK tyrosine kinase receptor (ALK) [3], [4], [5]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.C1156Y
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.60  Å
PDB: 5A9U
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.78
TM score: 0.9838
Amino acid change:
C1156Y
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
M
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1070
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M
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E
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L
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1080
|
L
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S
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K
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L
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R
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T
M
S
A
T
H
I
H
M
H
1090
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T
H
D
H
Y
H
N
N
P
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
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V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
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N
N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
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K
K
T
T
L
L
P
P
E
E
V
V
C
Y
S
S
E
E
Q
Q
1160
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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
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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
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A
A
G
G
G
G
D
D
L
L
K
K
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S
F
F
L
L
R
R
1210
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E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
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S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
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A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
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L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
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I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
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P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
G
1270
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D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
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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
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K
1310
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T
T
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D
T
T
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W
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L
L
1320
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W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
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Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
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E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
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M
M
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D
1350
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P
P
P
P
K
K
N
N
C
C
P
P
G
G
P
P
V
V
Y
Y
1360
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R
R
I
I
M
M
T
T
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C
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W
Q
Q
H
H
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Q
1370
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P
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E
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D
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N
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F
F
A
A
I
I
I
I
1380
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L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
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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
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Liquid biopsy assay; Next-generation sequencing assay; Circulating-free DNA assay; Digital PCR assay; Pyrosequencing analysis; Droplet digital PCR assay; Next generation deep sequencing assay
Experiment for
Drug Resistance		 Analysis of progression-free survival (PFS) assay; Overall and disease-free assay
Mechanism Description In contrast, cells expressing either the C1156Y or L1196M mutant form manifested a markedly reduced sensitivity to the drug (23836314; 20979470). By applying a base-pair specific error-weighted mutation calling algorithm (BASCA) that we developed for this assay, genomic DNA analysis from thirteen relapsed patients revealed three known crizotinib resistance mutations, C1156Y, L1196M and G1269A. Our assay demonstrates robust and sensitive detection of ALk kinase mutations in NSCLC tumor samples and aids in the elucidation of resistance mechanisms pertinent to the clinical setting.
References
Ref 1 miR-100-5p confers resistance to ALK tyrosine kinase inhibitors Crizotinib and Lorlatinib in EML4-ALK positive NSCLC. Biochem Biophys Res Commun. 2019 Apr 2;511(2):260-265. doi: 10.1016/j.bbrc.2019.02.016. Epub 2019 Feb 18.
Ref 2 The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res. 2010 Dec 15;70(24):10038-43. doi: 10.1158/0008-5472.CAN-10-2956. Epub 2010 Oct 28.
Ref 3 Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010 Oct 28;363(18):1704-14. doi: 10.1056/NEJMoa1008410. Epub 2010 Aug 29.
Ref 4 Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment. Genomics. 2013 Sep;102(3):157-62. doi: 10.1016/j.ygeno.2013.02.006. Epub 2013 Feb 20.
Ref 5 Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013 Aug;10(8):472-84. doi: 10.1038/nrclinonc.2013.110. Epub 2013 Jul 9.
Ref 6 AXL and SHC1 confer crizotinib resistance in patient-derived xenograft model of ALK-driven lung cancer. iScience. 2024 Aug 30;27(9):110846.
Ref 7 Identification of different ALK mutations in a pair of neuroblastoma cell lines established at diagnosis and relapse. Oncotarget. 2016 Dec 27;7(52):87301-87311. doi: 10.18632/oncotarget.13541.
Ref 8 The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014 Jun;4(6):662-673. doi: 10.1158/2159-8290.CD-13-0846. Epub 2014 Mar 27.
Ref 9 Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014 Aug;11(8):473-81. doi: 10.1038/nrclinonc.2014.104. Epub 2014 Jul 1.
Ref 10 Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. J Thorac Oncol. 2013 Apr;8(4):415-22. doi: 10.1097/JTO.0b013e318283dcc0.
Ref 11 Genomic Aberrations in Crizotinib Resistant Lung Adenocarcinoma Samples Identified by Transcriptome Sequencing. PLoS One. 2016 Apr 5;11(4):e0153065. doi: 10.1371/journal.pone.0153065. eCollection 2016.
Ref 12 Anaplastic lymphoma kinase (ALK) inhibitors in the treatment of ALK-driven lung cancers. Pharmacol Res. 2017 Mar;117:343-356. doi: 10.1016/j.phrs.2017.01.007. Epub 2017 Jan 8.
Ref 13 Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012 Feb 8;4(120):120ra17. doi: 10.1126/scitranslmed.3003316. Epub 2012 Jan 25.

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