Molecule Information

General Information of the Molecule (ID: Mol00224)
Name
ALK tyrosine kinase receptor (ALK) ,Homo sapiens
Molecule Type
Protein
Gene Name
ALK
Gene ID
238
Location
chr2:29192774-29921586[-]
Sequence
MGAIGLLWLLPLLLSTAAVGSGMGTGQRAGSPAAGPPLQPREPLSYSRLQRKSLAVDFVV
PSLFRVYARDLLLPPSSSELKAGRPEARGSLALDCAPLLRLLGPAPGVSWTAGSPAPAEA
RTLSRVLKGGSVRKLRRAKQLVLELGEEAILEGCVGPPGEAAVGLLQFNLSELFSWWIRQ
GEGRLRIRLMPEKKASEVGREGRLSAAIRASQPRLLFQIFGTGHSSLESPTNMPSPSPDY
FTWNLTWIMKDSFPFLSHRSRYGLECSFDFPCELEYSPPLHDLRNQSWSWRRIPSEEASQ
MDLLDGPGAERSKEMPRGSFLLLNTSADSKHTILSPWMRSSSEHCTLAVSVHRHLQPSGR
YIAQLLPHNEAAREILLMPTPGKHGWTVLQGRIGRPDNPFRVALEYISSGNRSLSAVDFF
ALKNCSEGTSPGSKMALQSSFTCWNGTVLQLGQACDFHQDCAQGEDESQMCRKLPVGFYC
NFEDGFCGWTQGTLSPHTPQWQVRTLKDARFQDHQDHALLLSTTDVPASESATVTSATFP
APIKSSPCELRMSWLIRGVLRGNVSLVLVENKTGKEQGRMVWHVAAYEGLSLWQWMVLPL
LDVSDRFWLQMVAWWGQGSRAIVAFDNISISLDCYLTISGEDKILQNTAPKSRNLFERNP
NKELKPGENSPRQTPIFDPTVHWLFTTCGASGPHGPTQAQCNNAYQNSNLSVEVGSEGPL
KGIQIWKVPATDTYSISGYGAAGGKGGKNTMMRSHGVSVLGIFNLEKDDMLYILVGQQGE
DACPSTNQLIQKVCIGENNVIEEEIRVNRSVHEWAGGGGGGGGATYVFKMKDGVPVPLII
AAGGGGRAYGAKTDTFHPERLENNSSVLGLNGNSGAAGGGGGWNDNTSLLWAGKSLQEGA
TGGHSCPQAMKKWGWETRGGFGGGGGGCSSGGGGGGYIGGNAASNNDPEMDGEDGVSFIS
PLGILYTPALKVMEGHGEVNIKHYLNCSHCEVDECHMDPESHKVICFCDHGTVLAEDGVS
CIVSPTPEPHLPLSLILSVVTSALVAALVLAFSGIMIVYRRKHQELQAMQMELQSPEYKL
SKLRTSTIMTDYNPNYCFAGKTSSISDLKEVPRKNITLIRGLGHGAFGEVYEGQVSGMPN
DPSPLQVAVKTLPEVCSEQDELDFLMEALIISKFNHQNIVRCIGVSLQSLPRFILLELMA
GGDLKSFLRETRPRPSQPSSLAMLDLLHVARDIACGCQYLEENHFIHRDIAARNCLLTCP
GPGRVAKIGDFGMARDIYRASYYRKGGCAMLPVKWMPPEAFMEGIFTSKTDTWSFGVLLW
EIFSLGYMPYPSKSNQEVLEFVTSGGRMDPPKNCPGPVYRIMTQCWQHQPEDRPNFAIIL
ERIEYCTQDPDVINTALPIEYGPLVEEEEKVPVRPKDPEGVPPLLVSQQAKREEERSPAA
PPPLPTTSSGKAAKKPTAAEISVRVPRGPAVEGGHVNMAFSQSNPPSELHKVHGSRNKPT
SLWNPTYGSWFTEKPTKKNNPIAKKEPHDRGNLGLEGSCTVPPNVATGRLPGASLLLEPS
SLTANMKEVPLFRLRHFPCGNVNYGYQQQGLPLEAATAPGAGHYEDTILKSKNSMNQPGP
    Click to Show/Hide
3D-structure
PDB ID
7LS0
Classification
Transferase/transferase activator
Method
X-ray diffraction
Resolution
3.05  Å
Function
Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK. Thinness gene involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity).
    Click to Show/Hide
Uniprot ID
ALK_HUMAN
Ensembl ID
ENSG00000171094
HGNC ID
HGNC:427
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Type(s) of Resistant Mechanism of This Molecule with Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
5 drug(s) in total
Click to Show/Hide the Full List of Drugs
Alectinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Neuroblastoma [ICD-11: 2A00.11] [1]
Resistant Disease Neuroblastoma [ICD-11: 2A00.11]
 Disease Info 
Resistant Drug Alectinib
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L
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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1120
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1180
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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.
Brigatinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [2]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G1269A (c.3806G>C)
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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1120
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E
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1140
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A
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C
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E
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1160
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N
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I
1180
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R
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1300
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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
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [3]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.L1196M (c.3586C>A)
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
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Y
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C
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F
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A
1100
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G
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K
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T
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S
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I
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D
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L
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1110
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E
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R
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1120
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R
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G
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E
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G
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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
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [4]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L (c.3520T>C)
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
Ceritinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [5]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Ceritinib
 Drug Info 
Molecule Alteration Missense mutation
p.L1196M
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
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Computerized tomography assay
Mechanism Description 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.
Crizotinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [5], [6], [7]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Missense mutation
p.G1269A
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
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.
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [8], [9]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Missense mutation
p.G1269A
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.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [10]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Missense mutation
p.L1196M
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.
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [11], [8]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Missense mutation
p.L1196M
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
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.
Disease Class: Neuroblastoma [ICD-11: 2A00.11] [1]
Resistant Disease Neuroblastoma [ICD-11: 2A00.11]
 Disease Info 
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L
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 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.
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [9]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Missense mutation
p.C1156Y
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
-
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
Y
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
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
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.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [6], [12], [13]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Missense mutation
p.C1156Y
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
-
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
Y
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
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
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.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Disease Class: Neuroblastoma [ICD-11: 2A00.11] [14]
Resistant Disease Neuroblastoma [ICD-11: 2A00.11]
 Disease Info 
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L
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 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.
Lorlatinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Neuroblastoma [ICD-11: 2A00.11] [1]
Resistant Disease Neuroblastoma [ICD-11: 2A00.11]
 Disease Info 
Resistant Drug Lorlatinib
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L
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 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.
Clinical Trial Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
AUY922
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [15]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug AUY922
 Drug Info 
Molecule Alteration Missense mutation
p.C1156Y (c.3467G>A)
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
-
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
Y
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
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
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Biochemical and Structural StudiesCo-crystallization analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay
Investigative Drug(s)
3 drug(s) in total
Click to Show/Hide the Full List of Drugs
AZD3463
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Neuroblastoma [ICD-11: 2A00.11] [16]
Sensitive Disease Neuroblastoma [ICD-11: 2A00.11]
 Disease Info 
Sensitive Drug AZD3463
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L (c.3520T>C)
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
Sk-N-AS cells Adrenal Homo sapiens (Human) CVCL_1700
SH-SY5Y cells Abdomen Homo sapiens (Human) CVCL_0019
NGP cells Lung Homo sapiens (Human) CVCL_2141
N b-19 cells N.A. Homo sapiens (Human) N.A.
In Vivo Model Orthotopic Mouse Model of NB Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay; Colony formation assay
Disease Class: Neuroblastoma [ICD-11: 2A00.11] [16]
Sensitive Disease Neuroblastoma [ICD-11: 2A00.11]
 Disease Info 
Sensitive Drug AZD3463
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L (c.3522C>A)
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
Sk-N-AS cells Adrenal Homo sapiens (Human) CVCL_1700
SH-SY5Y cells Abdomen Homo sapiens (Human) CVCL_0019
NGP cells Lung Homo sapiens (Human) CVCL_2141
N b-19 cells N.A. Homo sapiens (Human) N.A.
In Vivo Model Orthotopic Mouse Model of NB Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay; Colony formation assay
CEP-28122
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Neuroblastoma [ICD-11: 2A00.11] [17]
Sensitive Disease Neuroblastoma [ICD-11: 2A00.11]
 Disease Info 
Sensitive Drug CEP-28122
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L (c.3520T>C)
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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M
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1070
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L
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R
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1090
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T
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Y
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N
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N
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C
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F
A
A
1100
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G
G
K
K
T
T
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S
I
I
S
S
D
D
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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
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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
C
S
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E
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1160
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D
D
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E
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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
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H
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N
N
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1180
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V
V
R
R
C
C
I
I
G
G
V
V
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S
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L
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S
S
1190
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L
L
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P
R
R
F
F
I
I
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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
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P
R
R
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P
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S
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Q
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P
S
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1220
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S
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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
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R
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D
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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
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H
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F
F
I
I
H
H
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R
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D
1250
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I
I
A
A
A
A
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R
N
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L
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L
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C
1260
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G
G
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G
G
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A
A
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1270
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M
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1280
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Y
Y
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G
G
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G
C
C
A
A
1290
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L
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1300
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F
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M
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E
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G
I
I
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F
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1310
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D
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W
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F
F
G
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L
L
L
L
1320
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E
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F
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Y
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1330
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N
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1340
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E
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F
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V
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G
G
G
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1350
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N
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C
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1360
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W
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1370
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A
A
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I
I
1380
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L
L
E
E
R
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E
E
Y
Y
C
C
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1390
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D
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I
N
N
T
T
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L
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1400
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1410
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Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model SUP-M2 cells Colon Homo sapiens (Human) CVCL_2209
KARPAS-299 cells Peripheral blood Homo sapiens (Human) CVCL_1324
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The missense mutation p.F1174L (c.3520T>C) in gene ALK cause the sensitivity of CEP-28122 by aberration of the drug's therapeutic target
NVP-TAE684
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Neuroblastoma [ICD-11: 2A00.11] [1]
Resistant Disease Neuroblastoma [ICD-11: 2A00.11]
 Disease Info 
Resistant Drug NVP-TAE684
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L
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
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1070
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Q
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M
-
E
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L
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P
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1080
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R
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1090
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T
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D
Y
Y
N
N
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P
N
N
Y
Y
C
S
F
F
A
A
1100
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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
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T
T
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L
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I
1120
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R
R
G
G
L
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A
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E
1130
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Y
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E
G
G
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Q
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G
M
M
P
P
1140
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L
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V
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A
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1150
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1160
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1170
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1180
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1220
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1250
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1290
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1300
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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.
References
Ref 1 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 2 Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALKCancer Med. 2015 Jul;4(7):953-65. doi: 10.1002/cam4.413. Epub 2015 Feb 26.
Ref 3 Activity of brigatinib (BRG) in crizotinib (CRZ)-resistant ALK+ NSCLC patients (pts) according to ALK plasma mutation status.
Ref 4 Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and miceOncotarget. 2016 May 17;7(20):29011-22. doi: 10.18632/oncotarget.8508.
Ref 5 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 6 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 7 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 8 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 9 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 10 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 11 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.
Ref 12 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 13 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 14 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 15 Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198FN Engl J Med. 2016 Jan 7;374(1):54-61. doi: 10.1056/NEJMoa1508887. Epub 2015 Dec 23.
Ref 16 Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosisSci Rep. 2016 Jan 20;6:19423. doi: 10.1038/srep19423.
Ref 17 CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancersMol Cancer Ther. 2012 Mar;11(3):670-9. doi: 10.1158/1535-7163.MCT-11-0776. Epub 2011 Dec 27.

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