Molecule Information

General Information of the Molecule (ID: Mol00061)
Name
Epidermal growth factor receptor (EGFR) ,Homo sapiens
Synonyms
Proto-oncogene c-ErbB-1; Receptor tyrosine-protein kinase erbB-1; ERBB; ERBB1; HER1
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Molecule Type
Protein
Gene Name
EGFR
Gene ID
1956
Location
chr7:55019017-55211628[+]
Sequence
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEV
VLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALA
VLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDF
QNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGC
TGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYV
VTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFK
NCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAF
ENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKL
FGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCN
LLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVM
GENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVV
ALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGS
GAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGI
CLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAA
RNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSY
GVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPK
FRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQ
QGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTED
SIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLN
TVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRV
APQSSEFIGA
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3D-structure
PDB ID
7SYD
Classification
Signaling protein
Method
Electron microscopy
Resolution
3.10  Å
Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin. Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration. Plays a role in enhancing learning and memory performance.
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Uniprot ID
EGFR_HUMAN
Ensembl ID
ENSG00000146648
HGNC ID
HGNC:3236
        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
  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)
25 drug(s) in total
Click to Show/Hide the Full List of Drugs
Gefitinib
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [1]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Sensitive Drug Gefitinib
 Drug Info 
Molecule Alteration Expression
Down-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Non-small cell lung cancer
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 2.41E-78
Fold-change: -3.81E-01
Z-score: -2.43E+01
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
EGFR signaling pathway Inhibition hsa01521
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-133b suppresses the expression of EGFR, miR-133b transfection may modulate apoptosis, invasion and sensitivity to EGFR-TkI through the EGFR signaling pathways.
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [3]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Gefitinib
 Drug Info 
Molecule Alteration Expression
Down-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Lung adenocarcinoma
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 2.41E-78
Fold-change: -3.81E-01
Z-score: -2.43E+01
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
EGFR signaling pathway Inhibition hsa01521
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
16HBE cells Lung Homo sapiens (Human) CVCL_0112
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; EdU assay
Mechanism Description GAS5 was significantly downregulated in lung adenocarcinoma tissues compared with the paired adjacent non-tumorous tissue samples. Furthermore, lower GAS5 expression levels were associated with larger tumor sizes, poor tumor differentiation, and advanced pathological stages. However, GAS5 was almost equally expressed between benign tumors compared with the adjacent normal tissues. GAS5 was also overexpressed in EGFR-TkI sensitive cell lines compared with the resistant cell line. Using MTT, EdU incorporation, and colony formation assays, we showed that GAS5-expressing A549 cells displayed an elevated level of cell death. In addition to its pro-apoptotic effect in the A549 cell line, GAS5 overexpression also suppressed the growth of A549-derived tumors in nude mice treated with gefitinib. GAS5 overexpression was inversely correlated with the expression of the EGFR pathway and IGF-1R proteins.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [4]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Sensitive Drug Gefitinib
 Drug Info 
Molecule Alteration Expression
Down-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Non-small cell lung cancer
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 2.41E-78
Fold-change: -3.81E-01
Z-score: -2.43E+01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
CCD-19Lu cells Lung Homo sapiens (Human) CVCL_2382
H3255 cells Lung Homo sapiens (Human) CVCL_6831
MRC-5 cells Lung Homo sapiens (Human) CVCL_0440
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description microRNA-200a directly targets and downregulates egfr and c-met to inhibit migration, invasion, and gefitinib resistance in non-small cell lung cancer.
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [9]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Gefitinib
 Drug Info 
Molecule Alteration Expression
Up-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Lung cancer
The Studied Tissue Lung tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.65E-01
Fold-change: 1.45E-02
Z-score: 1.39E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
RGFR signaling pathway Inhibition hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description EGFR was negatively regulated by miR-7 mimic transfection, and downregulation of EGFR expression at the protein level largely correlated with elevated levels of miR-7 in the gefitinib-resistant cells. The results of the present study suggest that miR-7 may have central roles in the development of resistance to endocrine therapy in resistant cells through regulating the expression of EGFR in cancer cells.
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [41]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Sensitive Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.L858R
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.47  Å
PDB: 2ITV
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.90001
Amino acid change:
L858R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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710
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720
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740
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750
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760
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770
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780
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790
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800
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810
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830
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860
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870
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890
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920
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930
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950
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970
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1010
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1020
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ERK/MAPKsignaling pathway Activation hsa04210
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy; ATP-binding pocket affinity comparison assay
Mechanism Description The two most common EGFR-activating mutations are small in-frame deletions in exon 19 (particularly E746-A750del) and amino acid substitution in exon 21 (leucine to arginine at codon 858 (L858R)), which collectively account for >90% of known activating EGFR mutations.2 3 These two alterations are the best-characterised mutations conferring sensitivity to EGFR-tyrosine kinase inhibitor (EGFR-TkI) therapy, resulting in higher response rates (RR) (up to 70%) and longer median survival (up to 24-30 months) than those observed in patients with wild-type (WT) EGFR. The higher sensitivity of these mutations relays in an increased affinity of the ATP-binding pocket for EGFR-TkIs as compared with WT EGFR.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [41]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Sensitive Drug Gefitinib
 Drug Info 
Molecule Alteration Frameshift mutation
p.E746-A750del
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ERK/MAPKsignaling pathway Activation hsa04210
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy; ATP-binding pocket affinity comparison assay
Mechanism Description The two most common EGFR-activating mutations are small in-frame deletions in exon 19 (particularly E746-A750del) and amino acid substitution in exon 21 (leucine to arginine at codon 858 (L858R)), which collectively account for >90% of known activating EGFR mutations.2 3 These two alterations are the best-characterised mutations conferring sensitivity to EGFR-tyrosine kinase inhibitor (EGFR-TkI) therapy, resulting in higher response rates (RR) (up to 70%) and longer median survival (up to 24-30 months) than those observed in patients with wild-type (WT) EGFR. The higher sensitivity of these mutations relays in an increased affinity of the ATP-binding pocket for EGFR-TkIs as compared with WT EGFR.
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [7]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Expression
Up-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Non-small cell lung cancer
The Studied Tissue Lung tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 2.37E-11
Fold-change: 6.31E-01
Z-score: 7.28E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell colony Inhibition hsa05200
Cell viability Inhibition hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-138 inhibit the protein level of EGFR and reverses gefitinib resistance in lung cancer cells.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [8]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Expression
Up-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Non-small cell lung cancer
The Studied Tissue Lung tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 2.37E-11
Fold-change: 6.31E-01
Z-score: 7.28E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
Sk-MES-1 cells Lung Homo sapiens (Human) CVCL_0630
In Vivo Model Tumor xenograft in vivo model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Long Noncoding RNA LINC00460 promotes the gefitinib resistance of nonsmall cell lung cancer through EGFR by sponging miR-769-5p.
Disease Class: Lung cancer [ICD-11: 2C25.5] [53]
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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770
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780
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800
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830
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T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT signaling pathway Activation hsa04151
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Circulating-free DNA assay; Whole exome sequencing assay
Mechanism Description Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [41]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.C797S
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6JRX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.92164
Amino acid change:
C797S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
G
G
A
S
M
M
G
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
S
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
-
Q
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ERK/MAPKsignaling pathway Activation hsa04210
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy; ATP-binding pocket affinity comparison assay
Mechanism Description Known mechanisms are secondary resistance mutations occurring in the ATP-binding domain (such as T790M and C797S), mutation or amplification of bypass signallings (such as AXL, Hh, ERBb2, CRIPTO, etc), activating mutations in the downstream pathways (PI3k, AkT, MEk, RAF), low levels of mRNA or polymorphisms of the pro-apoptotic protein BIM, induction of a transcription programme for EMT and phenotypical changes, or induction of elevated tumour PD-L1 levels.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [42], [43], [44]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ERK/MAPKsignaling pathway Activation hsa04210
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy; ATP-binding pocket affinity comparison assay
Mechanism Description Known mechanisms are secondary resistance mutations occurring in the ATP-binding domain (such as T790M and C797S), mutation or amplification of bypass signallings (such as AXL, Hh, ERBb2, CRIPTO, etc), activating mutations in the downstream pathways (PI3k, AkT, MEk, RAF), low levels of mRNA or polymorphisms of the pro-apoptotic protein BIM, induction of a transcription programme for EMT and phenotypical changes, or induction of elevated tumour PD-L1 levels.
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [45], [46], [47]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
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		 Direct sequencing assay
Experiment for
Drug Resistance		 Overall and disease-free assay
Mechanism Description A secondary T790M mutation of EGFR accounted for half the tumors with acquired resistance to gefitinib in Japanese patients. Other drug-resistant secondary mutations are uncommon in the EGFR gene.
Disease Class: Lung squamous cell carcinoma [ICD-11: 2C25.3] [48], [49], [50]
Resistant Disease Lung squamous cell carcinoma [ICD-11: 2C25.3]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
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		 Computed tomography (CT) scanning assay; Bone scintigraphy assay; Magnetic resonance imaging assay
Mechanism Description C-Met amplification, epithelial-mesenchymal transition, and kRAS and BRAF mutations were ruled out as alternative resistance mechanisms in the T790M-negative lung rebiopsy, suggesting that alternative oncogene aberrations such as HER2/Neu amplification, hepatocyte growth factor release by the tumor microenvironment, or other unidentified pathways contributed to the TkI resistance that was observed in the primary lesion.
Disease Class: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7] [51]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
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		 MGB SNP detection kit assay; Mutation Detection assay
Experiment for
Drug Resistance		 Digital PCR assay
Mechanism Description Resistance mechanisms to EGFR-TkI therapy in EGFR-mutated NSCLC include secondary EGFR T790M mutation, c-Met amplification, PIk3CA mutation, and transformation to small-cell lung cancer.
Disease Class: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7] [38]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Low throughput experiment assay
Experiment for
Drug Resistance		 Progression-free survival assay
Mechanism Description 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. At the point of acquired resistance, the T790M substitution may be accompanied by amplification of the EGFR gene as well.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [39]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Next generation sequencing assay
Experiment for
Drug Resistance		 Multivariate analysis of overall or disease-free survival assay
Mechanism Description One example is the acquisition of the T790M substitution in the membrane receptor EGFR conferring resistance to gefitinb and erlotinib in lung cancer in approximately 50% of patients.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [45]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Cos-7 cells Lung Homo sapiens (Human) CVCL_0224
NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
Experiment for
Molecule Alteration		 qRT-PCR
Mechanism Description The DNA sequence of the EGFR gene in his tumor biopsy specimen at relapse revealed the presence of a second point mutation, resulting in threonine-to-methionine amino acid change at position 790 of EGFR. Structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [45]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Cos-7 cells Lung Homo sapiens (Human) CVCL_0224
NIH-3T3 cells Embryo Mus musculus (Mouse) CVCL_0594
Experiment for
Molecule Alteration		 qRT-PCR
Mechanism Description The DNA sequence of the EGFR gene in his tumor biopsy specimen at relapse revealed the presence of a second point mutation, resulting in threonine-to-methionine amino acid change at position 790 of EGFR. Structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [41]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.C797S+p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6JRX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.92164
Amino acid change:
C797S+T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
G
G
A
S
M
M
G
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
S
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
-
Q
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT signaling pathway Activation hsa04151
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
EGFR/TKLS mediated apoptosis signaling pathway Inhibition hsa01521
Epithelial mesenchymal transition signaling pathway Activation hsa01521
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy; ATP-binding pocket affinity comparison assay
Mechanism Description Several mechanisms of resistance have been described to EGFR-TkIs, such as the occurrence of secondary mutation (T790M, C797S), the activation of alternative signalling (Met, HGF, AXL, Hh, IGF-1R), the aberrance of the downstream pathways (AkT mutations, loss of PTEN), the impairment of the EGFR-TkIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism) and histological transformation.
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [52]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.D761Y
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct Sanger sequencing analysis
Experiment for
Drug Resistance		 CellTiter-Blue cell viability assay
Mechanism Description The T790M mutation is common in patients with acquired resistance. The limited spectrum of TkI-resistant mutations in EGFR, which binds to erlotinib in the active conformation, contrasts with a wider range of second-site mutations seen with acquired resistance to imatinib, which binds to ABL and kIT, respectively, in closed conformations. Collectively, our data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomic site and mode of binding to the kinase target.
Disease Class: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7] [38]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.L747S
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Low throughput experiment assay
Experiment for
Drug Resistance		 Progression-free survival assay
Mechanism Description 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: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7] [38]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Missense mutation
p.D761Y
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Low throughput experiment assay
Experiment for
Drug Resistance		 Progression-free survival assay
Mechanism Description 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] [21]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Gefitinib
 Drug Info 
Molecule Alteration Mutation
.
Experiment for
Drug Resistance		 Statistical analysis
Mechanism Description EGFR-TKI Rechallenge With Another TKI may be a useful treatment option after first-line osimertinib.
Paclitaxel
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: Non-small cell lung cancer [ICD-11: 2C25.Y] [2]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Sensitive Drug Paclitaxel
 Drug Info 
Molecule Alteration Expression
Down-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Non-small cell lung cancer
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 2.41E-78
Fold-change: -3.81E-01
Z-score: -2.43E+01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
95D cells Lung Homo sapiens (Human) CVCL_7110
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description Overexpression of miR-7 sensitizes NSCLC cells to PTX and inhibites EGFR expression in A549 cells.
Cisplatin
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: Non-small cell lung cancer [ICD-11: 2C25.Y] [5]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Sensitive Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Down-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Non-small cell lung cancer
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 2.41E-78
Fold-change: -3.81E-01
Z-score: -2.43E+01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description miR-21 mainly achieves drug resistance by inhibiting cisplatin-induced apoptosis, and its specific mechanisms include the following: (1) improving the expression level of EGFR and protecting the toxic effect of tumor cells during chemotherapy; (2) Increase the expression of LRP and decrease the effective concentration of the target drug through the barrier of drug transport between nucleus and cell; (3) Enhance the expression of multidrug resistance associated protein (MRP1) and assist in pumping chemotherapeutic drugs from the inside to the outside of the cell.
Docetaxel
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: Non-small cell lung cancer [ICD-11: 2C25.Y] [6]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Docetaxel
 Drug Info 
Molecule Alteration Expression
Up-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Non-small cell lung cancer
The Studied Tissue Lung tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 2.37E-11
Fold-change: 6.31E-01
Z-score: 7.28E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
EGFR signaling pathway Inhibition hsa01521
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description The transfection of miR 27b mimics led to downregulation of the expression levels of EGFR, whilst miR 27b inhibitors upregulated the expression levels of EGFR. Furthermore, it was demonstrated that the transfection of miR 27b mimics significantly suppressed the apoptosis and promote the viability of A549 human lung carcinoma cells. In line with this, the introduction of miR 27b inhibitors significantly induced apoptosis and inhibited the proliferation of A549 cells. These results indicate that miR 27b may promote NSCLC cell viability and enhance resistance to docetaxel treatment through direct inhibition of EGFR expression.
Vemurafenib
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: Melanoma [ICD-11: 2C30.0] [10]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Sensitive Drug Vemurafenib
 Drug Info 
Molecule Alteration Expression
Down-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Melanoma [ICD-11: 2C30]
The Specified Disease Melanoma
The Studied Tissue Skin
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.60E-01
Fold-change: -9.63E-02
Z-score: -1.44E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
MAPK/PI3K/AKT signaling pathway Inhibition hsa05235
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Mel-CV cells Skin Homo sapiens (Human) CVCL_S996
Experiment for
Molecule Alteration		 Immunohistochemical staining assay; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-7 expression was decreased in both VemR A375 and Mel-CVR melanoma cells and its low expression contributed to BRAFi resistance. Furthermore, by decreasing the expression levels of EGFR, IGF-1R and CRAF, miR-7 could inhibit the activation of RAS/RAF/MEk/ERk (MAPk) and PI3k/AkT pathway and partially reverse the resistance to BRAFi in VemR A375 melanoma cells.
Doxorubicin
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: Prostate cancer [ICD-11: 2C82.0] [11]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Prostate cancer [ICD-11: 2C82]
The Specified Disease Prostate cancer
The Studied Tissue Prostate
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 7.43E-04
Fold-change: -1.42E-01
Z-score: -3.79E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
In Vitro Model DU-145 cells Prostate Homo sapiens (Human) CVCL_0105
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description LncRNA LOXL1-AS1/miR-let-7a-5p/EGFR-related pathway regulates the doxorubicin resistance of prostate cancer DU-145 cells.
Trastuzumab
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: Breast cancer [ICD-11: 2C60.3] [12]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Sensitive Drug Trastuzumab
 Drug Info 
Molecule Alteration Expression
Down-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Breast cancer [ICD-11: 2C60]
The Specified Disease Breast cancer
The Studied Tissue Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.04E-65
Fold-change: -1.82E-01
Z-score: -2.10E+01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Colcount colony counter assay
Mechanism Description miR-7 suppression of HER2deta16 oncogenic activity is mediated through inactivation of Src kinase and suppression of EGFR expression implies that targeting these pathways would also suppress HER2deta16 tumorigenesis. HER2deta16 suppresses expression of the miR-7 tumor suppressor and reestablished miR-7 expression significantly inhibits HER2deta16 mediated tumor cell proliferation and migration and miR-7 sensitizes HER2deta16 expressing cells to trastuzumab treatment.
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.V292E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.I706T
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.R705G
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.L760F
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.K284E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.G696E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.A822V
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.V292M
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.P741S
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.G288D
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.E711K
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Temozolomide
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: Glioblastoma multiforme [ICD-11: 2A00.03] [13]
Sensitive Disease Glioblastoma multiforme [ICD-11: 2A00.03]
 Disease Info 
Sensitive Drug Temozolomide
 Drug Info 
Molecule Alteration Expression
Down-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Brain cancer [ICD-11: 2A00]
The Specified Disease Neuroectodermal tumor
The Studied Tissue Brainstem tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.84E-08
Fold-change: -2.34E-01
Z-score: -1.06E+01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model U251 cells Brain Homo sapiens (Human) CVCL_0021
U87 cells Brain Homo sapiens (Human) CVCL_0022
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Luciferase reporter assay
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometric analysis
Mechanism Description miR181b modulates chemosensitivity of glioblastoma multiforme cells to temozolomide by targeting the epidermal growth factor receptor.
Afatinib
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: Lung adenocarcinoma [ICD-11: 2C25.0] [15], [16], [17]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Afatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
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		 Exon sequencing assay
Experiment for
Drug Resistance		 Progression-free and post-progression survival asaay
Mechanism Description T790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired resistance mechanism. First-generation EGFR TkI exposure did not influence the prevalence of T790M in lung cancer acquired resistance to afatinib.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [18], [19], [20]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Afatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
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K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
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I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
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K
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I
I
T
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D
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F
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G
G
L
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A
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860
|
K
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L
L
L
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G
G
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E
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870
|
H
H
A
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G
G
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K
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880
|
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L
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890
|
I
I
Y
Y
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S
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D
D
V
V
W
W
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S
900
|
Y
Y
G
G
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L
L
M
M
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T
910
|
F
F
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Y
Y
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D
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G
I
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P
P
920
|
A
A
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L
L
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930
|
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940
|
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950
|
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960
|
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970
|
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980
|
V
V
I
I
Q
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G
G
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H
H
L
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990
|
P
P
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S
P
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T
D
D
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S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
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D
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M
D
D
D
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1010
|
V
V
V
V
D
D
A
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D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
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		 Directional sequencing assay; Direct sequencing assay; Sanger sequencing assay
Experiment for
Drug Resistance		 Progression-free and post-progression survival asaay; Analysis of progression-free survival (PFS) assay; Overall survival assay
Mechanism Description The identification of T790M as acquired resistance mechanism was clinically feasible. Although T790M had no prognostic or predictive role in the present study, further research is necessary to identify patients with T790M-mutant tumors who might benefit from newly developed T790M-specific TkIs.T790M is likely a common resistance mechanism in patients treated with first-line afatinib. Although repeat biopsies at progression are crucial in elucidating resistance mechanisms, this study suggests that clinical and technical issues often limit their feasibility, highlighting the importance of developing.
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [21]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Afatinib
 Drug Info 
Molecule Alteration Mutation
.
Experiment for
Drug Resistance		 Statistical analysis
Mechanism Description EGFR-TKI Rechallenge With Another TKI may be a useful treatment option after first-line osimertinib.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Esophagogastric cancer [ICD-11: 2B71.1] [22]
Sensitive Disease Esophagogastric cancer [ICD-11: 2B71.1]
 Disease Info 
Sensitive Drug Afatinib
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Identified from the Human Clinical Data
Mechanism Description In summary, we find that concurrent amplification of EGFR and ERBB2 is associated with response to the HER kinase inhibitor afatinib in patients with trastuzumab-refractory EG cancer. Heterogeneous uptake of 89Zr-trastuzumab measured noninvasively by PET was associated with disease progression. Analyses of multiple disease sites sampled at the time of disease progression indicated several potential mediators of afatinib resistance, including loss of EGFR amplification and gain of MET amplification.
Brigatinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [23]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration Missense mutation
p.L858R (c.2573T>G)
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.47  Å
PDB: 2ITV
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.90001
Amino acid change:
L858R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
M
-
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
T
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
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K
I
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T
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D
D
F
F
G
G
L
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A
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860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
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Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
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P
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880
|
W
W
M
M
A
A
L
L
E
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S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
-
Q
-
G
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
U937 cells Blood Homo sapiens (Human) CVCL_0007
H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
SUP-M2 cells Colon Homo sapiens (Human) CVCL_2209
KARPAS-299 cells Peripheral blood Homo sapiens (Human) CVCL_1324
SU-DHL-1 cells Pleural effusion Homo sapiens (Human) CVCL_0538
L-82 cells Pleural effusion Homo sapiens (Human) CVCL_2098
HCC78 cells Pleural effusion Homo sapiens (Human) CVCL_2061
H838 cells Lymph node Homo sapiens (Human) CVCL_1594
H-4-II-E cells Liver Rattus norvegicus (Rat) CVCL_0284
H358 cells Lung Homo sapiens (Human) CVCL_1559
H2228 cells Lung Homo sapiens (Human) CVCL_1543
DEL cells Pleural effusion Homo sapiens (Human) CVCL_1170
In Vivo Model SCID beige mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Brigatinib is the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses.
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [23]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Brigatinib
 Drug Info 
Molecule Alteration IF-deletion
p.E746_A750delELREA (c.2236_2250del15)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
U937 cells Blood Homo sapiens (Human) CVCL_0007
H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
SUP-M2 cells Colon Homo sapiens (Human) CVCL_2209
KARPAS-299 cells Peripheral blood Homo sapiens (Human) CVCL_1324
SU-DHL-1 cells Pleural effusion Homo sapiens (Human) CVCL_0538
L-82 cells Pleural effusion Homo sapiens (Human) CVCL_2098
HCC78 cells Pleural effusion Homo sapiens (Human) CVCL_2061
H838 cells Lymph node Homo sapiens (Human) CVCL_1594
H-4-II-E cells Liver Rattus norvegicus (Rat) CVCL_0284
H358 cells Lung Homo sapiens (Human) CVCL_1559
H2228 cells Lung Homo sapiens (Human) CVCL_1543
DEL cells Pleural effusion Homo sapiens (Human) CVCL_1170
In Vivo Model SCID beige mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Brigatinib is the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses.
Cetuximab
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Metastatic colorectal cancer [ICD-11: 2D85.0] [24]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease Info 
Resistant Drug Cetuximab
 Drug Info 
Molecule Alteration Missense mutation
p.S492R
Wild Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 3C09
Mutant Type Structure Method: X-ray diffraction Resolution: 2.80  Å
PDB: 6B3S
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.58
TM score: 0.98774
Amino acid change:
S492R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
L
L
E
E
E
E
310
|
K
K
K
K
V
V
C
C
N
N
G
G
I
I
G
G
I
I
G
G
320
|
E
E
F
F
K
K
D
D
S
S
L
L
S
S
I
I
N
N
A
A
330
|
T
T
N
N
I
I
K
K
H
H
F
F
K
K
N
N
C
C
T
T
340
|
S
S
I
I
S
S
G
G
D
D
L
L
H
H
I
I
L
L
P
P
350
|
V
V
A
A
F
F
R
R
G
G
D
D
S
S
F
F
T
T
H
H
360
|
T
T
P
P
P
P
L
L
D
D
P
P
Q
Q
E
E
L
L
D
D
370
|
I
I
L
L
K
K
T
T
V
V
K
K
E
E
I
I
T
T
G
G
380
|
F
F
L
L
L
L
I
I
Q
Q
A
A
W
W
P
P
E
E
N
N
390
|
R
R
T
T
D
D
L
L
H
H
A
A
F
F
E
E
N
N
L
L
400
|
E
E
I
I
I
I
R
R
G
G
R
R
T
T
K
K
Q
Q
H
H
410
|
G
G
Q
Q
F
F
S
S
L
L
A
A
V
V
V
V
S
S
L
L
420
|
N
N
I
I
T
T
S
S
L
L
G
G
L
L
R
R
S
S
L
L
430
|
K
K
E
E
I
I
S
S
D
D
G
G
D
D
V
V
I
I
I
I
440
|
S
S
G
G
N
N
K
K
N
N
L
L
C
C
Y
Y
A
A
N
N
450
|
T
T
I
I
N
N
W
W
K
K
K
K
L
L
F
F
G
G
T
T
460
|
S
S
G
G
Q
Q
K
K
T
T
K
K
I
I
I
I
S
R
N
N
470
|
R
R
G
G
E
E
N
N
S
S
C
C
K
K
A
A
T
T
G
G
480
|
Q
Q
V
V
C
C
H
H
A
A
L
L
C
C
S
S
P
P
E
E
490
|
G
G
C
C
W
W
G
G
P
P
E
E
P
P
R
R
D
D
C
C
500
|
V
V
S
S
C
C
R
R
N
N
V
V
S
S
R
R
G
G
R
R
510
|
E
E
C
C
V
V
D
D
K
K
H
H
H
H
H
H
H
H
H
H
520
|
H
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Circulating-free DNA assay; Standard-of-care sequencing assay
Mechanism Description K-RAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs).
Disease Class: Colorectal cancer [ICD-11: 2B91.1] [25]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Resistant Drug Cetuximab
 Drug Info 
Molecule Alteration Missense mutation
p.G465E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Colon cells Colon Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy assay
Mechanism Description Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Colorectal cancer [ICD-11: 2B91.1] [26]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Sensitive Drug Cetuximab
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model SW480 cells Colon Homo sapiens (Human) CVCL_0546
HCT116 cells Colon Homo sapiens (Human) CVCL_0291
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description microRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation.
Dacomitinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [27]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Dacomitinib
 Drug Info 
Molecule Alteration IF-insertion
p.Y764_V765insHH (c.2292_2293insCATCAT)
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [27]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Dacomitinib
 Drug Info 
Molecule Alteration Duplication
p.A767_V769 (c.2299_2307)
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [27]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Dacomitinib
 Drug Info 
Molecule Alteration Duplication
p.S768_D770 (c.2302_2310)
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [28]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Missense mutation
p.L858R (c.2573T>G)
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.47  Å
PDB: 2ITV
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.90001
Amino acid change:
L858R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
M
-
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
T
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
R
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
-
Q
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [27]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Complex-indel
p.D770_770delinsGY (c.2308_2310delinsGGTTAT)
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [27]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Duplication
p.N771_H773 (c.2311_2319)
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [29]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Missense mutation
p.E709K (c.2125G>A)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
myelomonocyti cells Bone marrow Homo sapiens (Human) N.A.
macrophage-like cells N.A. N.A. N.A.
IL3-dependent murine pro-B cells Blood Homo sapiens (Human) N.A.
Balb/C mouse leukemia cells Blood Mus musculus (Mouse) CVCL_9099
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [29]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Complex-indel
p.E709_T710delinsD (c.2127_2129delAAC)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
myelomonocyti cells Bone marrow Homo sapiens (Human) N.A.
macrophage-like cells N.A. N.A. N.A.
IL3-dependent murine pro-B cells Blood Homo sapiens (Human) N.A.
Balb/C mouse leukemia cells Blood Mus musculus (Mouse) CVCL_9099
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [30]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Missense mutation
p.G719S (c.2155G>A)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [30]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Missense mutation
p.G719C (c.2155G>T)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [30]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Missense mutation
p.G719A (c.2156G>C)
Experimental Note Identified from the Human Clinical Data
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [29]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration Missense mutation
p.G719A (c.2156G>C)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
myelomonocyti cells Bone marrow Homo sapiens (Human) N.A.
macrophage-like cells N.A. N.A. N.A.
IL3-dependent murine pro-B cells Blood Homo sapiens (Human) N.A.
Balb/C mouse leukemia cells Blood Mus musculus (Mouse) CVCL_9099
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [27]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration IF-insertion
p.P772_H773insPNP (c.2317_2318insCTAACCCTC)
Experimental Note Identified from the Human Clinical Data
In Vitro Model NSCLC cells Lung Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; SDS-PAGE assay
Experiment for
Drug Resistance		 MTS assay; Crystal violet staining assay
Mechanism Description Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [31]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Dacomitinib
 Drug Info 
Molecule Alteration IF-deletion
p.G729_D761 (c.2185_2283)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Lung N.A.
Dasatinib
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: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Dasatinib
 Drug Info 
Molecule Alteration Missense mutation
p.E711K
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Erlotinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [33], [34], [35]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
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		 Direct sequencing assay
Experiment for
Drug Resistance		 Overall and disease-free assay
Mechanism Description Among patients with acquired resistance to EGFR TkIs, the presence of T790M defines a clinical subset with a relatively favorable prognosis and more indolent progression.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [36], [37]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
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		 Direct sequencing assay
Experiment for
Drug Resistance		 Computed tomography assay
Mechanism Description In addition, three (8%) patients acquired EGFR amplifications in their resistant specimens, all of which also acquired the classic T790M EGFR mutation. Moreover, in two cases with high-level EGFR amplification (>10-fold), it was clear by comparison of the peak heights on the SNaPshot chromatogram that the T790M allele was the amplified allele. They have identified several resistance mechanisms, two of which-EGFR mutation T790M and MET amplification have been validated in the clinic.
Disease Class: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7] [38]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Low throughput experiment assay
Experiment for
Drug Resistance		 Progression-free survival assay
Mechanism Description 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. At the point of acquired resistance, the T790M substitution may be accompanied by amplification of the EGFR gene as well.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [39]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Next generation sequencing assay
Experiment for
Drug Resistance		 Multivariate analysis of overall or disease-free survival assay
Mechanism Description One example is the acquisition of the T790M substitution in the membrane receptor EGFR conferring resistance to gefitinb and erlotinib in lung cancer in approximately 50% of patients.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [40]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Wnt signaling pathway Activation hsa04310
mTOR signaling pathway Activation hsa04150
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
H2170 cells Lung Homo sapiens (Human) CVCL_1535
Experiment for
Molecule Alteration		 Low throughput experiment assay
Experiment for
Drug Resistance		 MTT cell viability assay
Mechanism Description H1975 cells are positive for the T790M EGFR mutation, which confers resistance to current EGFR TkI therapies.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [41]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Missense mutation
p.C797S+p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6JRX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.92164
Amino acid change:
C797S+T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
G
G
A
S
M
M
G
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
S
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
-
Q
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT signaling pathway Activation hsa04151
Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
EGFR/TKLS mediated apoptosis signaling pathway Inhibition hsa01521
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy; ATP-binding pocket affinity comparison assay
Mechanism Description Several mechanisms of resistance have been described to EGFR-TkIs, such as the occurrence of secondary mutation (T790M, C797S), the activation of alternative signalling (Met, HGF, AXL, Hh, IGF-1R), the aberrance of the downstream pathways (AkT mutations, loss of PTEN), the impairment of the EGFR-TkIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism) and histological transformation.
Disease Class: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7] [38]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Missense mutation
p.D761Y
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Low throughput experiment assay
Experiment for
Drug Resistance		 Progression-free survival assay
Mechanism Description 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: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7] [38]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Missense mutation
p.L747S
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Low throughput experiment assay
Experiment for
Drug Resistance		 Progression-free survival assay
Mechanism Description 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] [21]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Erlotinib
 Drug Info 
Molecule Alteration Mutation
.
Experiment for
Drug Resistance		 Statistical analysis
Mechanism Description EGFR-TKI Rechallenge With Another TKI may be a useful treatment option after first-line osimertinib.
Icotinib hydrochloride
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] [18], [19], [20]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Icotinib hydrochloride
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
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		 Directional sequencing assay; Direct sequencing assay
Experiment for
Drug Resistance		 Progression-free and post-progression survival asaay
Mechanism Description The identification of T790M as acquired resistance mechanism was clinically feasible. Although T790M had no prognostic or predictive role in the present study, further research is necessary to identify patients with T790M-mutant tumors who might benefit from newly developed T790M-specific TkIs.
Imatinib
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: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.E711K
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Lapatinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Missense mutation
p.V292E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Missense mutation
p.R705G
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Missense mutation
p.L760F
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Missense mutation
p.K284E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Missense mutation
p.I706T
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G696E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Missense mutation
p.A822V
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Missense mutation
p.V292M
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Missense mutation
p.P741S
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G288D
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Lapatinib
 Drug Info 
Molecule Alteration Missense mutation
p.E711K
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Nilotinib
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: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Nilotinib
 Drug Info 
Molecule Alteration Missense mutation
p.E711K
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Olmutinib
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: Lung adenocarcinoma [ICD-11: 2C25.0] [54]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Olmutinib
 Drug Info 
Molecule Alteration Missense mutation
p.C797S
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6JRX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.92164
Amino acid change:
C797S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
G
G
A
S
M
M
G
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
S
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
-
Q
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Computed tomography assay; Progression-free survival assay
Mechanism Description A recent preclinical study reported that EGFR C797S, L718Q, and L844V mutations cause resistance to both WZ4002 and CO-1686 but only EGFR C797S leads to AZD9291 resistance, suggesting that C797S can serve as acquired resistance to irreversible pyrimidine-based EGFR inhibitors given the similar chemical structure of third-generation EGFR TkIs.
Osimertinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [55]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Osimertinib
 Drug Info 
Molecule Alteration Missense mutation
p.C797S
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6JRX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.92164
Amino acid change:
C797S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
G
G
A
S
M
M
G
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
S
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
-
Q
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Cell-free plasma DNA assay; Next generation assay; Droplet digital PCR assay
Experiment for
Drug Resistance		 Progression-free survival assay
Mechanism Description Acquired EGFR C797S mediates resistance to AZD9291 in advanced non-small cell lung cancer harboring EGFR T790M.
Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [56]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Osimertinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Sanger sequencing assay; Fluorescence in situ hybridization assay; Real-time polymerase chain reaction assay; Targeted exome sequencing assay
Experiment for
Drug Resistance		 Computed tomography assay
Mechanism Description Acquired resistance mechanisms of AZD9291 in patients with EGFRT790M-mutant NSCLC who failed treatment with first-generation EGFR TkIs include the loss of EGFRT790M-mutant clones plus alternative pathway activation or histologic transformation and EGFR ligand-dependent activation.
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [21]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Osimertinib
 Drug Info 
Molecule Alteration Mutation
.
Experiment for
Drug Resistance		 Statistical analysis
Mechanism Description EGFR-TKI Rechallenge With Another TKI may be a useful treatment option after first-line osimertinib.
Panitumumab
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Metastatic colorectal cancer [ICD-11: 2D85.0] [24]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease Info 
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Missense mutation
p.S492R
Wild Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 3C09
Mutant Type Structure Method: X-ray diffraction Resolution: 2.80  Å
PDB: 6B3S
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.58
TM score: 0.98774
Amino acid change:
S492R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
L
L
E
E
E
E
310
|
K
K
K
K
V
V
C
C
N
N
G
G
I
I
G
G
I
I
G
G
320
|
E
E
F
F
K
K
D
D
S
S
L
L
S
S
I
I
N
N
A
A
330
|
T
T
N
N
I
I
K
K
H
H
F
F
K
K
N
N
C
C
T
T
340
|
S
S
I
I
S
S
G
G
D
D
L
L
H
H
I
I
L
L
P
P
350
|
V
V
A
A
F
F
R
R
G
G
D
D
S
S
F
F
T
T
H
H
360
|
T
T
P
P
P
P
L
L
D
D
P
P
Q
Q
E
E
L
L
D
D
370
|
I
I
L
L
K
K
T
T
V
V
K
K
E
E
I
I
T
T
G
G
380
|
F
F
L
L
L
L
I
I
Q
Q
A
A
W
W
P
P
E
E
N
N
390
|
R
R
T
T
D
D
L
L
H
H
A
A
F
F
E
E
N
N
L
L
400
|
E
E
I
I
I
I
R
R
G
G
R
R
T
T
K
K
Q
Q
H
H
410
|
G
G
Q
Q
F
F
S
S
L
L
A
A
V
V
V
V
S
S
L
L
420
|
N
N
I
I
T
T
S
S
L
L
G
G
L
L
R
R
S
S
L
L
430
|
K
K
E
E
I
I
S
S
D
D
G
G
D
D
V
V
I
I
I
I
440
|
S
S
G
G
N
N
K
K
N
N
L
L
C
C
Y
Y
A
A
N
N
450
|
T
T
I
I
N
N
W
W
K
K
K
K
L
L
F
F
G
G
T
T
460
|
S
S
G
G
Q
Q
K
K
T
T
K
K
I
I
I
I
S
R
N
N
470
|
R
R
G
G
E
E
N
N
S
S
C
C
K
K
A
A
T
T
G
G
480
|
Q
Q
V
V
C
C
H
H
A
A
L
L
C
C
S
S
P
P
E
E
490
|
G
G
C
C
W
W
G
G
P
P
E
E
P
P
R
R
D
D
C
C
500
|
V
V
S
S
C
C
R
R
N
N
V
V
S
S
R
R
G
G
R
R
510
|
E
E
C
C
V
V
D
D
K
K
H
H
H
H
H
H
H
H
H
H
520
|
H
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Circulating-free DNA assay; Standard-of-care sequencing assay
Mechanism Description K-RAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs).
Disease Class: Colorectal cancer [ICD-11: 2B91.1] [25]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Missense mutation
p.G465E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Colon cells Colon Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Liquid biopsy assay
Mechanism Description Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Metastatic colorectal cancer [ICD-11: 2D85.0] [57]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease Info 
Resistant Drug Panitumumab
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
EGFR signaling pathway Activation hsa01521
ERBB2/MET/IGF-1R signalling pathway Activation hsa04520
RAF/KRAS/MEK signaling pathway Activation hsa04010
PI3K/AKT/mTOR signaling pathway Activation hsa04151
Experiment for
Drug Resistance		 Progression-free survival (PFS) analysis; Overall survival (OS) analysis
Mechanism Description Cetuximab and panitumumab are monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) that are effective agents for metastatic colorectal cancer (mCRC). The mechanisms of resistance refer to intrinsic and extrinsic alterations of tumours. The intrinsic mechanisms include EGFR ligand overexpression, EGFR alteration, RAS/RAF/PI3K gene mutations, ERBB2/MET/IGF-1R activation, metabolic remodelling, microsatellite instability and autophagy. Extrinsic alterations mainly disrupt the tumour microenvironment, specifically immune cells, cancer-associated fibroblasts (CAFs) and angiogenesis.
Pemetrexed
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: Non-small cell lung cancer [ICD-11: 2C25.Y] [51]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Pemetrexed
 Drug Info 
Molecule Alteration Missense mutation
p.T790M
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
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		 MGB SNP detection kit assay; Mutation Detection assay
Experiment for
Drug Resistance		 Digital PCR assay
Mechanism Description Resistance mechanisms to EGFR-TkI therapy in EGFR-mutated NSCLC include secondary EGFR T790M mutation, c-Met amplification, PIk3CA mutation, and transformation to small-cell lung cancer.
Pertuzumab
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: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Pertuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.V292E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Pertuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.R705G
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Pertuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.L760F
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Pertuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.K284E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Pertuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.I706T
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Pertuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.G696E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Pertuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.A822V
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Pertuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.V292M
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Pertuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.P741S
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Pertuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.G288D
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Pertuzumab
 Drug Info 
Molecule Alteration Missense mutation
p.E711K
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Trastuzumab emtansine
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: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab emtansine
 Drug Info 
Molecule Alteration Missense mutation
p.V292E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab emtansine
 Drug Info 
Molecule Alteration Missense mutation
p.R705G
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab emtansine
 Drug Info 
Molecule Alteration Missense mutation
p.L760F
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab emtansine
 Drug Info 
Molecule Alteration Missense mutation
p.K284E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab emtansine
 Drug Info 
Molecule Alteration Missense mutation
p.I706T
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab emtansine
 Drug Info 
Molecule Alteration Missense mutation
p.G696E
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab emtansine
 Drug Info 
Molecule Alteration Missense mutation
p.A822V
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab emtansine
 Drug Info 
Molecule Alteration Missense mutation
p.V292M
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab emtansine
 Drug Info 
Molecule Alteration Missense mutation
p.P741S
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Disease Class: HER2 positive breast cancer [ICD-11: 2C60.8] [32]
Resistant Disease HER2 positive breast cancer [ICD-11: 2C60.8]
 Disease Info 
Resistant Drug Trastuzumab emtansine
 Drug Info 
Molecule Alteration Missense mutation
p.G288D
Experimental Note Identified from the Human Clinical Data
In Vitro Model Plasma Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Circulating-free DNA assay
Experiment for
Drug Resistance		 Positron emission tomography/Computed tomography assay
Mechanism Description Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.
Vandetanib
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: Lung adenocarcinoma [ICD-11: 2C25.0] [58]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Vandetanib
 Drug Info 
Molecule Alteration Missense mutation
p.L858R (c.2573T>G)
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.47  Å
PDB: 2ITV
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.90001
Amino acid change:
L858R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
M
-
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
T
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
R
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
-
Q
-
G
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
H1650 cells Pleural effusion Homo sapiens (Human) CVCL_4V01
Calu-6 cells Lung Homo sapiens (Human) CVCL_0236
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.L858R (c.2573T>G) in gene EGFR cause the sensitivity of Vandetanib by aberration of the drug's therapeutic target
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [59]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Vandetanib
 Drug Info 
Molecule Alteration IF-deletion
p.E746_A750delELREA (c.2236_2250del15)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model LOVO cells Colon Homo sapiens (Human) CVCL_0399
A431 cells Skin Homo sapiens (Human) CVCL_0037
PC-14 cells Lung Homo sapiens (Human) CVCL_1640
WiDR cells Colon Homo sapiens (Human) CVCL_2760
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
SkOV3 cells Ovary Homo sapiens (Human) CVCL_0532
PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The if-deletion p.E746_A750delELREA (c.2236_2250del15) in gene EGFR cause the sensitivity of Vandetanib by unusual activation of pro-survival pathway.
Patented Agent(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Abivertinib
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: Lung adenocarcinoma [ICD-11: 2C25.0] [60]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Abivertinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M (c.2369C>T)
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Hela cells Cervix uteri Homo sapiens (Human) CVCL_0030
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
BEAS-2B cells Bronchus Homo sapiens (Human) CVCL_0168
A431 cells Skin Homo sapiens (Human) CVCL_0037
NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
HT1080 cells Acetabulum Homo sapiens (Human) CVCL_0317
In Vivo Model Nu/Nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 WST-1 assay
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [60]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Abivertinib
 Drug Info 
Molecule Alteration IF-deletion
p.E746_A750delELREA (c.2236_2250del15)
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Hela cells Cervix uteri Homo sapiens (Human) CVCL_0030
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
BEAS-2B cells Bronchus Homo sapiens (Human) CVCL_0168
A431 cells Skin Homo sapiens (Human) CVCL_0037
NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
HT1080 cells Acetabulum Homo sapiens (Human) CVCL_0317
In Vivo Model Nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis; ELISA assay
Experiment for
Drug Resistance		 WST-1 assay
Clinical Trial Drug(s)
4 drug(s) in total
Click to Show/Hide the Full List of Drugs
Nazartinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [61]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug Nazartinib
 Drug Info 
Molecule Alteration Duplication
p.N771_H773 (c.2311_2319)
Experimental Note Identified from the Human Clinical Data
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
HaCaT cells Tongue Homo sapiens (Human) CVCL_0038
A431 cells Skin Homo sapiens (Human) CVCL_0037
H3255 cells Lung Homo sapiens (Human) CVCL_6831
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [61]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Nazartinib
 Drug Info 
Molecule Alteration Duplication
p.S768_D770 (c.2302_2310)
Experimental Note Identified from the Human Clinical Data
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
HaCaT cells Tongue Homo sapiens (Human) CVCL_0038
A431 cells Skin Homo sapiens (Human) CVCL_0037
H3255 cells Lung Homo sapiens (Human) CVCL_6831
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [61]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Nazartinib
 Drug Info 
Molecule Alteration Duplication
p.N771_H773 (c.2311_2319)
Experimental Note Identified from the Human Clinical Data
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
HaCaT cells Tongue Homo sapiens (Human) CVCL_0038
A431 cells Skin Homo sapiens (Human) CVCL_0037
H3255 cells Lung Homo sapiens (Human) CVCL_6831
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor
Selumetinib
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] [62]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.T790M (c.2369C>T)
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
In Vivo Model BALB/C nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Immunohistochemistry assay
Experiment for
Drug Resistance		 MTT assay
AUY922
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [63]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.A763_Y764insFQEA (c.2290_2291insTTCAAGAGGCAT)
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. The non-geldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis.
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [63]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.Y764_V765insHH (c.2292_2293insCATCAT)
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. The non-geldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis.
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [63]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration Duplication
p.S768_D770 (c.2302_2310)
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. The non-geldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis.
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [63]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.P772_H773insGNP (c.2316_2317insGGTAACCCT)
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. The non-geldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis.
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [63]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration Duplication
p.H773 (c.2317_2319)
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. The non-geldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [63]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.A763_Y764insFQEA (c.2290_2291insTTCAAGAGGCAT)
Experimental Note Identified from the Human Clinical Data
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
NCI-H3255 cells Lung Homo sapiens (Human) CVCL_6831
BID007 cells Pleural effusion Homo sapiens (Human) CVCL_W890
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter Glo assay; IC50 assay
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration Duplication
p.A767_V769 (c.2299_2307)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration Duplication
p.S768_D770 (c.2302_2310)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.A767_V769dupASV (c.2308_2309insCAAGCGTAG)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration Duplication
p.D770_P772 (c.2308_2316)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.D770_N771insGV (c.2310_2311insGGTGTA)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.D770_N771insGF (c.2310_2311insGGTTTT)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.S768_D770dupSVD (c.2311_2312insGCGTAGACA)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration Duplication
p.P772_H773 (c.2314_2319)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.P772_H773insYNP (c.2315_2316insTTATAACCC)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration Duplication
p.H773 (c.2317_2319)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.H773_V774insAH (c.2320_2321insCACATG)
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.A763_Y764insFQEA
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.A767_V774ins
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.V769_D770insASV
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.A770_N771insNPY
Experimental Note Identified from the Human Clinical Data
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [64]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Sensitive Drug AUY922
 Drug Info 
Molecule Alteration IF-insertion
p.D770_N771insSVD
Experimental Note Identified from the Human Clinical Data
Naquotinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [65]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Naquotinib
 Drug Info 
Molecule Alteration IF-insertion
p.Y764_V765insHH (c.2292_2293insCATCAT)
Experimental Note Identified from the Human Clinical Data
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
H3255 cells Lung Homo sapiens (Human) CVCL_6831
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9ER cells N.A. N.A. N.A.
BID007 cells Pleural effusion Homo sapiens (Human) CVCL_W890
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 MTS assay; FACS assay
Mechanism Description There is a mechanism for resistance associated with EGFR Y764_V765insHH mutation, one of the most resistant mutations. We demonstrated that in Y764_V765insHH, histidine residues inserted in the Val765 and Met766 positions upregulated the EGFR kinase activity and caused steric insensitivity to the particular EGFR-TKIs.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [65]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Naquotinib
 Drug Info 
Molecule Alteration Missense mutation
p.L858R (c.2573T>G)
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.47  Å
PDB: 2ITV
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.90001
Amino acid change:
L858R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
M
-
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
T
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
R
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
-
Q
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
H3255 cells Lung Homo sapiens (Human) CVCL_6831
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9ER cells N.A. N.A. N.A.
BID007 cells Pleural effusion Homo sapiens (Human) CVCL_W890
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 MTS assay; FACS assay
Mechanism Description There is a mechanism for resistance associated with EGFR Y764_V765insHH mutation, one of the most resistant mutations. We demonstrated that in Y764_V765insHH, histidine residues inserted in the Val765 and Met766 positions upregulated the EGFR kinase activity and caused steric insensitivity to the particular EGFR-TKIs.
Disease- and Tissue-specific Abundances of This Molecule
ICD Disease Classification 02
Click to Show/Hide the Resistance Disease of This Class
Brain cancer [ICD-11: 2A00]
Click to Show/Hide
Differential expression of molecule in resistant diseases
The Studied Tissue Nervous tissue
The Specified Disease Brain cancer
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 8.30E-26; Fold-change: 6.21E-02; Z-score: 1.32E-01
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
The Studied Tissue Brainstem tissue
The Specified Disease Glioma
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 2.09E-05; Fold-change: 3.96E-01; Z-score: 1.90E+02
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
The Studied Tissue White matter
The Specified Disease Glioma
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 6.32E-04; Fold-change: 3.88E-01; Z-score: 1.69E+00
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
The Studied Tissue Brainstem tissue
The Specified Disease Neuroectodermal tumor
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 1.84E-08; Fold-change: -1.12E+00; Z-score: -4.45E+00
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
Lung cancer [ICD-11: 2C25]
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Differential expression of molecule in resistant diseases
The Studied Tissue Lung
The Specified Disease Lung cancer
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 1.65E-01; Fold-change: -4.23E-02; Z-score: -8.52E-02
The Expression Level of Disease Section Compare with the Adjacent Tissue p-value: 1.58E-03; Fold-change: -2.14E-01; Z-score: -3.48E-01
Molecule expression in the normal tissue adjacent to the diseased tissue of patients
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the normal section of the tissue adjacent to the disease section
Download Molecule expression data of patients in the disease section of the tissue
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Melanoma [ICD-11: 2C30]
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Differential expression of molecule in resistant diseases
The Studied Tissue Skin
The Specified Disease Melanoma
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 1.60E-01; Fold-change: -3.39E-01; Z-score: -2.30E-01
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
Breast cancer [ICD-11: 2C60]
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Differential expression of molecule in resistant diseases
The Studied Tissue Breast tissue
The Specified Disease Breast cancer
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 1.04E-65; Fold-change: -8.87E-01; Z-score: -1.53E+00
The Expression Level of Disease Section Compare with the Adjacent Tissue p-value: 2.77E-16; Fold-change: -9.49E-01; Z-score: -1.79E+00
Molecule expression in the normal tissue adjacent to the diseased tissue of patients
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the normal section of the tissue adjacent to the disease section
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
Prostate cancer [ICD-11: 2C82]
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Differential expression of molecule in resistant diseases
The Studied Tissue Prostate
The Specified Disease Prostate cancer
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 7.43E-04; Fold-change: -5.92E-01; Z-score: -8.22E-01
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
Tissue-specific Molecule Abundances in Healthy Individuals
Click to Show/Hide the Molecule Abundances
Download the Tissue-Specific Variation(s) Profile
References
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