Drug Information

Drug (ID: DG00101) and It's Reported Resistant Information
Name
Erlotinib
Synonyms
Erlotinin; Tarceva; Erlotinib Base; OSI 744; R 1415; CP 358,774; CP-358774; Erlotinib(Tarceva); Tarceva (TN); CP-358,774; Erlotinib, OS-774; N-(3-ethynylphenyl)[6,7-bis(2-methoxyethoxy)quinazolin-4-yl]amine; N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine; N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine; N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-Quinazolinamine; [6,7-BIS(2-METHOXY-ETHOXY)QUINAZOLINE-4-YL]-(3-ETHYNYLPHENYL)AMINE; [6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine; 4-[(3-Ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline; 4-[(3-ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline
    Click to Show/Hide
Indication
In total 3 Indication(s)
Lung cancer [ICD-11: 2C25]
Approved
[1]
Pancreatic cancer [ICD-11: 2C10]
Phase 3
[1]
Colon cancer [ICD-11: 2B90]
Phase 2
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Lactic acidosis [ICD-11: 5C73]
[2]
Lung cancer [ICD-11: 2C25]
[3], [4], [5]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
Lung cancer [ICD-11: 2C25]
[7]
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
[8]
Target Epidermal growth factor receptor (EGFR) EGFR_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C22H23N3O4
IsoSMILES
COCCOC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=CC(=C3)C#C)OCCOC
InChI
1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
InChIKey
AAKJLRGGTJKAMG-UHFFFAOYSA-N
PubChem CID
176870
ChEBI ID
CHEBI:114785
TTD Drug ID
D07POC
VARIDT ID
DR00558
DrugBank ID
DB00530
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  RTDM: Regulation by the Disease Microenvironment
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Lung cancer [ICD-11: 2C25]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Histone-lysine N-methyltransferase EZH1 (EZH1) [9]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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: 5.76E-01
Fold-change: 4.58E-03
Z-score: 5.60E-01
Experimental Note Identified from the Human Clinical Data
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 Western blot analysis; qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells, miR17-5p could inhibit the mRNA and protein levels of EZH1.
Key Molecule: phosphoinositide-3-dependent protein kinase 1 (PDPK1) [1]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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: 8.73E-09
Fold-change: 3.48E-02
Z-score: 5.92E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
miR1183/PDPk1 signaling pathway Activation hsa05206
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
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR; Luciferase reporter assay
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description Hsa_circ_0004015 formed by CDk14 gene inhibited the expression of miR-1183, which could disinhibit the PDPk1 expression from miR-1183, ultimately resulted in the promotion of cell proliferation, invasion, and TkI inhibitor drug resistance of NSCLC cells.
Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [7]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Notch/miR223/FBXW7 signaling pathway Regulation N.A.
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
293T cells Breast Homo sapiens (Human) CVCL_0063
HCC827/ER cells Lung Homo sapiens (Human) CVCL_EJ07
Experiment for
Molecule Alteration		 Dual luciferase reporter assay; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Colony formation assay; Flow cytometric apoptosis assay
Mechanism Description Sensitivity of non-small cell lung cancer to erlotinib is regulated by the Notch/miR223/FBXW7 pathway. Blocking either the Akt or Notch signaling pathway and reducing miR223 expression resulted in decreased resistance in HCC827/ER cells, miR223 enhanced resistance to erlotinib by down-regulating FBXW7 expression.
Key Molecule: Hepatocyte growth factor receptor (MET) [21]
Resistant Disease EGFR-mutant lung adenocarcinoma [ICD-11: 2C25.1]
 Disease Info 
Molecule Alteration Structural variation
Amplification
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MET signaling pathway Activation hsa04150
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Fluorescence in situ hybridization assay
Experiment for
Drug Resistance		 Computed tomography assay
Mechanism Description These two cases already had MET amplification before EGFR-TkI treatment. In contrast, our patient had an EGFR mutation and then newly developed MET amplification after erlotinib therapy, suggesting that MET amplification occurred as a mechanism of acquired resistance.
Key Molecule: PI3-kinase alpha (PIK3CA) [16]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Mutation
.
 Molecule Info 
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.
Key Molecule: Hepatocyte growth factor receptor (MET) [16]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Molecule Alteration Structural variation
Copy number gain
 Molecule Info 
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.
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [16]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Molecule Alteration Structural variation
Copy number gain
 Molecule Info 
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.
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [16]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Molecule Alteration Mutation
.
 Molecule Info 
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.
Key Molecule: Tyrosine-protein kinase ITK/TSK (ITK) [16]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Molecule Alteration Mutation
.
 Molecule Info 
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.
Key Molecule: PI3-kinase alpha (PIK3CA) [17]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Molecule Alteration Mutation
.
 Molecule Info 
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 Quantification of allele fractions in plasma identified increased representation of mutantalleles in association with emergence of therapy resistance. These included an activating mutation in PIk3CA.
Key Molecule: Hepatocyte growth factor receptor (MET) [22]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Expression
Activation
 Molecule Info 
Cell Pathway Regulation HGF-Met signaling pathway Regulation N.A.
Mechanism Description Aberrant Met amplification and HGF-Met signaling pathway activation have been proven to be the main mechanism of acquired resistance of EGFR inhibition by small molecules, such as erlotinib and gefitinib.
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: Forkhead box protein O1 (FOXO1) [11]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
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: 9.16E-10
Fold-change: -9.51E-02
Z-score: -6.37E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell viability Activation hsa05200
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
HCC4006 cells Lung Homo sapiens (Human) CVCL_1269
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description LncRNA RP11-838N2.4 is required for the erlotinib resistance of NSCLC cells and FOXO1 could bind to the promoter region of LncRNA RP11 838N2.4, resulting in its silencing through the recruitment of histone deacetylase.
Key Molecule: Long non-protein coding RNA (RP11-838N2.4) [11]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Deacetylation
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell viability Activation hsa05200
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
HCC4006 cells Lung Homo sapiens (Human) CVCL_1269
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description LncRNA RP11-838N2.4 is required for the erlotinib resistance of NSCLC cells and FOXO1 could bind to the promoter region of LncRNA RP11 838N2.4, resulting in its silencing through the recruitment of histone deacetylase.
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [3], [4], [5]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
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
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A
A
L
L
L
L
R
R
I
I
L
L
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E
E
710
|
T
T
E
E
F
F
K
K
K
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V
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L
L
G
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720
|
S
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A
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F
F
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Y
Y
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730
|
L
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740
|
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L
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R
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750
|
A
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P
K
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A
A
N
N
K
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E
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I
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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
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L
L
I
I
790
|
T
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Q
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L
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M
M
P
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F
F
G
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C
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L
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L
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800
|
D
D
Y
Y
V
V
R
R
E
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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
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Q
850
|
H
H
V
V
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I
I
T
T
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
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Y
Y
870
|
H
H
A
A
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G
G
G
G
K
K
V
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P
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I
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880
|
W
W
M
M
A
A
L
L
E
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S
I
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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
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K
K
930
|
G
G
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L
L
P
P
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Q
P
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C
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940
|
T
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D
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V
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Y
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M
M
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M
M
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950
|
C
C
W
W
M
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A
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960
|
K
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970
|
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980
|
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990
|
P
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N
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F
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1000
|
A
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1010
|
V
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1020
|
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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.
Key Molecule: Epidermal growth factor receptor (EGFR) [14], [15]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
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
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710
|
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T
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K
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720
|
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730
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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
|
T
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L
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F
F
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800
|
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H
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N
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810
|
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N
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W
W
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820
|
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Y
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830
|
D
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R
R
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L
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H
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840
|
A
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850
|
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860
|
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870
|
H
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G
G
G
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K
K
V
V
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P
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880
|
W
W
M
M
A
A
L
L
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S
I
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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.
Key Molecule: Epidermal growth factor receptor (EGFR) [16]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [17]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [18]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [19]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.C797S+p.T790M
 Molecule Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [16]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Molecule Alteration Missense mutation
p.D761Y
 Molecule Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [16]
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
Molecule Alteration Missense mutation
p.L747S
 Molecule Info 
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.
Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [20]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
EGFR-K745_E746insIPVAIK; Exon 19 deletion, L858R, L861Q, G719S, A763_Y764insFQEA
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K-Akt signaling pathway Inhibition hsa04151
In Vitro Model Ba/F3 murine cells Bone marrow Homo sapiens (Human) N.A.
Bosc23 cells Fetal kidney Homo sapiens (Human) CVCL_4401
Experiment for
Molecule Alteration		 GeneSeq assay
Experiment for
Drug Resistance		 Cell proliferation assay; Immunoblotting assay
Mechanism Description Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.
Key Molecule: Epidermal growth factor receptor (EGFR) [6]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experiment for
Drug Resistance		 Statistical analysis
Mechanism Description EGFR-TKI Rechallenge With Another TKI may be a useful treatment option after first-line osimertinib.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-1183 [1]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
miR1183/PDPk1 signaling pathway Activation hsa05206
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
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description Hsa_circ_0004015 formed by CDk14 gene inhibited the expression of miR-1183, which could disinhibit the PDPk1 expression from miR-1183, ultimately resulted in the promotion of cell proliferation, invasion, and TkI inhibitor drug resistance of NSCLC cells.
Key Molecule: hsa_circ_0004015 [1]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
miR1183/PDPk1 signaling pathway Activation hsa05206
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
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description Hsa_circ_0004015 formed by CDk14 gene inhibited the expression of miR-1183, which could disinhibit the PDPk1 expression from miR-1183, ultimately resulted in the promotion of cell proliferation, invasion, and TkI inhibitor drug resistance of NSCLC cells.
Key Molecule: hsa-mir-223 [7]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Notch/miR223/FBXW7 signaling pathway Regulation N.A.
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
293T cells Breast Homo sapiens (Human) CVCL_0063
HCC827/ER cells Lung Homo sapiens (Human) CVCL_EJ07
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Colony formation assay; Flow cytometric apoptosis assay
Mechanism Description Sensitivity of non-small cell lung cancer to erlotinib is regulated by the Notch/miR223/FBXW7 pathway. Blocking either the Akt or Notch signaling pathway and reducing miR223 expression resulted in decreased resistance in HCC827/ER cells, miR223 enhanced resistance to erlotinib by down-regulating FBXW7 expression.
Key Molecule: hsa-miR-17-5p [9]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells, miR17-5p could inhibit the mRNA and protein levels of EZH1.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [20]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
EGFR-K745_E746insIPVAIK; Exon 19 deletion, L858R, L861Q, G719S, A763_Y764insFQEA
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K-Akt signaling pathway Inhibition hsa04151
In Vitro Model Ba/F3 murine cells Bone marrow Homo sapiens (Human) N.A.
Bosc23 cells Fetal kidney Homo sapiens (Human) CVCL_4401
Experiment for
Molecule Alteration		 GeneSeq assay
Experiment for
Drug Resistance		 Cell proliferation assay; Immunoblotting assay
Mechanism Description Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-23a [23]
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
PTEN/PI3K/AKT signaling pathway Inhibition hsa05235
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometric analysis
Mechanism Description Inhibition of miR23a increases the sensitivity of lung cancer stem cells to erlotinib through PTEN/PI3k/Akt pathway. Transfection with miR23a inhibitors promoted the erlotinib-dependent inhibition of PI3k/AkT pathway, thus, suppressing the proliferation and inducing apoptosis in PC9 CSCs.
Key Molecule: hsa-mir-214 [24]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
HCC827/ER cells Lung Homo sapiens (Human) CVCL_EJ07
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Transwell invasion assay; MTS assay
Mechanism Description Down-regulation of miR214 reverses erlotinib resistance in non-small-cell lung cancer through up-regulating LHX6 expression.
Key Molecule: hsa-miR-30a-5p [25]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Annexin V-FITC Apoptosis assay; CytoSelect Cell Invasion Assay; Wound healing assay
Mechanism Description miR30a-5p overexpression targets the EGFR and insulin-like growth factor receptor-1 (IGF-1R) signaling pathways to overcome the drug resistance. The combination of EGFR and IGF-1R inhibitors treatment could block the PI3k/AkT signaling pathway.
Key Molecule: hsa-mir-223 [26]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
IGF-1R/AKT/S6 signaling pathway Regulation N.A.
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-223 inhibits IGF-1R/Akt/S6 signaling, and this effect is reversed by the exogenous expression of IGF-1. Overexpression of miR-223 enhances the sensitivity of PC-9/ER cells to erlotinib by inducing apoptosis.
Key Molecule: hsa-mir-34 [27]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation 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
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCl-H226 cells Lung Homo sapiens (Human) CVCL_1544
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 AlamarBlue assay
Mechanism Description A majority of NSCLC and other cancers previously not suited for erlotinib may prove sensitive to the drug when used in combination with a miR-34a-based therapy.
Key Molecule: hsa-let-7c [28]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Hedgehog signaling pathway Inhibition hsa04340
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-200b and let-7c, inhibited the TGF-beta1-mediated resistance of NSCLC cells to erlotinib.
Key Molecule: hsa-mir-200b [28]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Hedgehog signaling pathway Inhibition hsa04340
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-200b and let-7c, inhibited the TGF-beta1-mediated resistance of NSCLC cells to erlotinib.
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: ERBB receptor feedback inhibitor 1 (ERRFI1) [29]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
TGF-Beta/miR200/MIG6 signaling pathway Inhibition hsa05206
In Vitro Model Calu3 cells Lung Homo sapiens (Human) CVCL_0609
H292 cells Lung Homo sapiens (Human) CVCL_0455
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCl-H226 cells Lung Homo sapiens (Human) CVCL_1544
NCl-H1437 cells Lung Homo sapiens (Human) CVCL_1472
H1703 cells Lung Homo sapiens (Human) CVCL_1490
H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu6 cells Lung Homo sapiens (Human) CVCL_0236
H1838 cells Lung Homo sapiens (Human) CVCL_1499
H1915 cells Lung Homo sapiens (Human) CVCL_1505
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Alamar Blue assay
Mechanism Description The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.
Key Molecule: hsa-mir-200a [29]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
TGF-Beta/miR200/MIG6 signaling pathway Inhibition hsa05206
In Vitro Model Calu3 cells Lung Homo sapiens (Human) CVCL_0609
H292 cells Lung Homo sapiens (Human) CVCL_0455
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCl-H226 cells Lung Homo sapiens (Human) CVCL_1544
NCl-H1437 cells Lung Homo sapiens (Human) CVCL_1472
H1703 cells Lung Homo sapiens (Human) CVCL_1490
H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu6 cells Lung Homo sapiens (Human) CVCL_0236
H1838 cells Lung Homo sapiens (Human) CVCL_1499
H1915 cells Lung Homo sapiens (Human) CVCL_1505
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR; RT-PCR
Experiment for
Drug Resistance		 Alamar Blue assay
Mechanism Description The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.
Key Molecule: hsa-mir-200b [29]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
TGF-Beta/miR200/MIG6 signaling pathway Inhibition hsa05206
In Vitro Model Calu3 cells Lung Homo sapiens (Human) CVCL_0609
H292 cells Lung Homo sapiens (Human) CVCL_0455
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCl-H226 cells Lung Homo sapiens (Human) CVCL_1544
NCl-H1437 cells Lung Homo sapiens (Human) CVCL_1472
H1703 cells Lung Homo sapiens (Human) CVCL_1490
H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu6 cells Lung Homo sapiens (Human) CVCL_0236
H1838 cells Lung Homo sapiens (Human) CVCL_1499
H1915 cells Lung Homo sapiens (Human) CVCL_1505
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR; RT-PCR
Experiment for
Drug Resistance		 Alamar Blue assay
Mechanism Description The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.
Key Molecule: hsa-mir-200c [29]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
TGF-Beta/miR200/MIG6 signaling pathway Inhibition hsa05206
In Vitro Model Calu3 cells Lung Homo sapiens (Human) CVCL_0609
H292 cells Lung Homo sapiens (Human) CVCL_0455
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCl-H226 cells Lung Homo sapiens (Human) CVCL_1544
NCl-H1437 cells Lung Homo sapiens (Human) CVCL_1472
H1703 cells Lung Homo sapiens (Human) CVCL_1490
H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu6 cells Lung Homo sapiens (Human) CVCL_0236
H1838 cells Lung Homo sapiens (Human) CVCL_1499
H1915 cells Lung Homo sapiens (Human) CVCL_1505
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR; RT-PCR
Experiment for
Drug Resistance		 Alamar Blue assay
Mechanism Description The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Phosphatase and tensin homolog (PTEN) [23]
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
PTEN/PI3K/AKT signaling pathway Inhibition hsa05235
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Luciferase reporter assay; Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Flow cytometric analysis
Mechanism Description Inhibition of miR23a increases the sensitivity of lung cancer stem cells to erlotinib through PTEN/PI3k/Akt pathway. Transfection with miR23a inhibitors promoted the erlotinib-dependent inhibition of PI3k/AkT pathway, thus, suppressing the proliferation and inducing apoptosis in PC9 CSCs.
Key Molecule: LIM/homeobox protein Lhx6 (LHX6) [24]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
HCC827/ER cells Lung Homo sapiens (Human) CVCL_EJ07
Experiment for
Molecule Alteration		 Dual luciferase reporter assay; Western blot analysis
Experiment for
Drug Resistance		 Transwell invasion assay; MTS assay
Mechanism Description Down-regulation of miR214 reverses erlotinib resistance in non-small-cell lung cancer through up-regulating LHX6 expression.
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [26]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
IGF-1R/AKT/S6 signaling pathway Regulation N.A.
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-223 inhibits IGF-1R/Akt/S6 signaling, and this effect is reversed by the exogenous expression of IGF-1. Overexpression of miR-223 enhances the sensitivity of PC-9/ER cells to erlotinib by inducing apoptosis.
Pancreatic cancer [ICD-11: 2C10]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Fibroblast growth factor 2 (FGF1) [10]
Sensitive Disease Pancreatic cancer [ICD-11: 2C10.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Pancreatic cancer [ICD-11: 2C10]
The Specified Disease Pancreatic cancer
The Studied Tissue Pancreas
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 3.42E-01
Fold-change: -4.67E-02
Z-score: -9.76E-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
FGF/FGFR signaling pathway Inhibition hsa01521
In Vitro Model MIA PaCa-2 cells Pancreas Homo sapiens (Human) CVCL_0428
SW1990 cells Pancreas Homo sapiens (Human) CVCL_1723
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-497 suppressed cells proliferation, decreased the percentage of S phase cells, re-sensitized cells to gemcitabine and erlotinib, and attenuated migration and invasion capacities. Furthermore, fibroblast growth factor 2 and fibroblast growth factor receptor 1 were confirmed as miR-497 targets. Overexpression of miR-497 inhibited tumor growth in vivo. Additionally, miR-497 expression was significantly downregulated in pancreatic cancer tissues compared with tumor-adjacent samples. Low expression of miR-497 was an independent adverse prognostic factor of pancreatic cancer. miR-497 plays a role in modulating the malignant phenotype and chemosensitivity of pancreatic cancer cells by directly inhibition of FGF2 and FGFR1 expression.
Key Molecule: Fibroblast growth factor receptor 1 (FGFR1) [10]
Sensitive Disease Pancreatic cancer [ICD-11: 2C10.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Pancreatic cancer [ICD-11: 2C10]
The Specified Disease Pancreatic cancer
The Studied Tissue Pancreas
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.09E-02
Fold-change: -1.00E-01
Z-score: -2.85E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
FGF/FGFR signaling pathway Inhibition hsa01521
In Vitro Model MIA PaCa-2 cells Pancreas Homo sapiens (Human) CVCL_0428
SW1990 cells Pancreas Homo sapiens (Human) CVCL_1723
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-497 suppressed cells proliferation, decreased the percentage of S phase cells, re-sensitized cells to gemcitabine and erlotinib, and attenuated migration and invasion capacities. Furthermore, fibroblast growth factor 2 and fibroblast growth factor receptor 1 were confirmed as miR-497 targets. Overexpression of miR-497 inhibited tumor growth in vivo. Additionally, miR-497 expression was significantly downregulated in pancreatic cancer tissues compared with tumor-adjacent samples. Low expression of miR-497 was an independent adverse prognostic factor of pancreatic cancer. miR-497 plays a role in modulating the malignant phenotype and chemosensitivity of pancreatic cancer cells by directly inhibition of FGF2 and FGFR1 expression.
Key Molecule: Ephrin type-A receptor 2 (EPHA2) [12]
Sensitive Disease Pancreatic cancer [ICD-11: 2C10.3]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
In Vitro Model BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
Capan-1 cells Pancreas Homo sapiens (Human) CVCL_0237
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description miR-124 overexpression was able to sensitize the response of Capan-1 cells to erlotinib through inhibiting EphA2.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-124 [12]
Sensitive Disease Pancreatic cancer [ICD-11: 2C10.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
In Vitro Model BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
Capan-1 cells Pancreas Homo sapiens (Human) CVCL_0237
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description miR-124 overexpression was able to sensitize the response of Capan-1 cells to erlotinib through inhibiting EphA2.
Key Molecule: hsa-mir-497 [10]
Sensitive Disease Pancreatic cancer [ICD-11: 2C10.3]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
FGF/FGFR signaling pathway Inhibition hsa01521
In Vitro Model MIA PaCa-2 cells Pancreas Homo sapiens (Human) CVCL_0428
SW1990 cells Pancreas Homo sapiens (Human) CVCL_1723
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-497 suppressed cells proliferation, decreased the percentage of S phase cells, re-sensitized cells to gemcitabine and erlotinib, and attenuated migration and invasion capacities. Furthermore, fibroblast growth factor 2 and fibroblast growth factor receptor 1 were confirmed as miR-497 targets. Overexpression of miR-497 inhibited tumor growth in vivo. Additionally, miR-497 expression was significantly downregulated in pancreatic cancer tissues compared with tumor-adjacent samples. Low expression of miR-497 was an independent adverse prognostic factor of pancreatic cancer. miR-497 plays a role in modulating the malignant phenotype and chemosensitivity of pancreatic cancer cells by directly inhibition of FGF2 and FGFR1 expression.
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [8]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Duplication
p.Y772_A775 (c.2314_2325)/p.A775_G776insYVMA
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [8]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Complex-indel
p.G776_776delinsVC (c.2326_2328delinsGTATGT)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [8]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Duplication
p.G778_P780 (c.2332_2340)/p.780_Y781insGSP
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Sanger cDNA sequencing assay
Experiment for
Drug Resistance		 CCK-8 assay
Liver cancer [ICD-11: 2C12]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [13]
Sensitive Disease Cholangiocarcinoma [ICD-11: 2C12.00]
 Disease Info 
Molecule Alteration phosphorylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model CCA-GemR cells Bile duct Homo sapiens (Human) N.A.
KKU-213A-GemR cells Bile duct Homo sapiens (Human) N.A.
KKU-213B-GemR cells Bile duct Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 Cell cycle distribution assay; Colony formation assay
Mechanism Description The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.
Bladder cancer [ICD-11: 2C94]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: ERBB receptor feedback inhibitor 1 (ERRFI1) [29]
Sensitive Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
TGF-Beta/miR200/MIG6 signaling pathway Inhibition hsa05206
In Vitro Model Calu3 cells Lung Homo sapiens (Human) CVCL_0609
H292 cells Lung Homo sapiens (Human) CVCL_0455
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCl-H226 cells Lung Homo sapiens (Human) CVCL_1544
NCl-H1437 cells Lung Homo sapiens (Human) CVCL_1472
H1703 cells Lung Homo sapiens (Human) CVCL_1490
H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu6 cells Lung Homo sapiens (Human) CVCL_0236
H1838 cells Lung Homo sapiens (Human) CVCL_1499
H1915 cells Lung Homo sapiens (Human) CVCL_1505
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Alamar Blue assay
Mechanism Description The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.
Key Molecule: hsa-mir-200a [29]
Sensitive Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
TGF-Beta/miR200/MIG6 signaling pathway Inhibition hsa05206
In Vitro Model Calu3 cells Lung Homo sapiens (Human) CVCL_0609
H292 cells Lung Homo sapiens (Human) CVCL_0455
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCl-H226 cells Lung Homo sapiens (Human) CVCL_1544
NCl-H1437 cells Lung Homo sapiens (Human) CVCL_1472
H1703 cells Lung Homo sapiens (Human) CVCL_1490
H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu6 cells Lung Homo sapiens (Human) CVCL_0236
H1838 cells Lung Homo sapiens (Human) CVCL_1499
H1915 cells Lung Homo sapiens (Human) CVCL_1505
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR; RT-PCR
Experiment for
Drug Resistance		 Alamar Blue assay
Mechanism Description The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.
Key Molecule: hsa-mir-200b [29]
Sensitive Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
TGF-Beta/miR200/MIG6 signaling pathway Inhibition hsa05206
In Vitro Model Calu3 cells Lung Homo sapiens (Human) CVCL_0609
H292 cells Lung Homo sapiens (Human) CVCL_0455
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCl-H226 cells Lung Homo sapiens (Human) CVCL_1544
NCl-H1437 cells Lung Homo sapiens (Human) CVCL_1472
H1703 cells Lung Homo sapiens (Human) CVCL_1490
H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu6 cells Lung Homo sapiens (Human) CVCL_0236
H1838 cells Lung Homo sapiens (Human) CVCL_1499
H1915 cells Lung Homo sapiens (Human) CVCL_1505
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR; RT-PCR
Experiment for
Drug Resistance		 Alamar Blue assay
Mechanism Description The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.
Key Molecule: hsa-mir-200c [29]
Sensitive Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
TGF-Beta/miR200/MIG6 signaling pathway Inhibition hsa05206
In Vitro Model Calu3 cells Lung Homo sapiens (Human) CVCL_0609
H292 cells Lung Homo sapiens (Human) CVCL_0455
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
NCI-H358 cells Lung Homo sapiens (Human) CVCL_1559
NCl-H226 cells Lung Homo sapiens (Human) CVCL_1544
NCl-H1437 cells Lung Homo sapiens (Human) CVCL_1472
H1703 cells Lung Homo sapiens (Human) CVCL_1490
H23 cells Lung Homo sapiens (Human) CVCL_1547
Calu6 cells Lung Homo sapiens (Human) CVCL_0236
H1838 cells Lung Homo sapiens (Human) CVCL_1499
H1915 cells Lung Homo sapiens (Human) CVCL_1505
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR; RT-PCR
Experiment for
Drug Resistance		 Alamar Blue assay
Mechanism Description The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.
Head and neck cancer [ICD-11: 2D42]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-34 [30]
Sensitive Disease Head and neck cancer [ICD-11: 2D42.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
In Vitro Model HN5 cells Neck Homo sapiens (Human) CVCL_8128
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description Expression of the tumor suppressor miR-34a was reduced in HN5-ER cells and increasing its expression abrogated Axl expression and reversed erlotinib resistance.
ICD-05: Endocrine/nutritional/metabolic diseases
Click to Show/Hide the Resistance Disease of This Class
Lactic acidosis [ICD-11: 5C73]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Protein kinase C (PRKC) [2]
Resistant Disease Lactic acidosis [ICD-11: 5C73.Z]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell migration Activation hsa04670
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The resistance might occur by several mechanisms, including epigenetic regulation, drug target alteration, multidrug resistance, cancer cell metabolic alteration, or TME factors.
Key Molecule: Protein kinase C (PRKC) [2]
Resistant Disease Lactic acidosis [ICD-11: 5C73.Z]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell migration Activation hsa04670
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The resistance might occur by several mechanisms, including epigenetic regulation, drug target alteration, multidrug resistance, cancer cell metabolic alteration, or TME factors.
References
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Ref 2 l-lactic acidosis confers insensitivity to PKC inhibitors by competing for uptake via monocarboxylate transporters .J Cell Physiol. 2022 Jan;237(1):934-948. doi: 10.1002/jcp.30570. Epub 2021 Sep 1. 10.1002/jcp.30570
Ref 3 Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011 Mar 15;17(6):1616-22. doi: 10.1158/1078-0432.CCR-10-2692. Epub 2010 Dec 6.
Ref 4 A noninvasive system for monitoring resistance to epidermal growth factor receptor tyrosine kinase inhibitors with plasma DNA. J Thorac Oncol. 2011 Oct;6(10):1639-48. doi: 10.1097/JTO.0b013e31822956e8.
Ref 5 Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations. Cancer. 2013 Dec 15;119(24):4325-32. doi: 10.1002/cncr.28364. Epub 2013 Sep 16.
Ref 6 Real-World Study of EGFR-TKI Rechallenge With Another TKI After First-Line Osimertinib Discontinuation in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: A Subset Analysis of the Reiwa Study. Thorac Cancer. 2025 Jan;16(2):e15507.
Ref 7 Sensitivity of non-small cell lung cancer to erlotinib is regulated by the Notch/miR-223/FBXW7 pathway. Biosci Rep. 2017 Jun 21;37(3):BSR20160478. doi: 10.1042/BSR20160478. Print 2017 Jun 30.
Ref 8 Activity of a novel HER2 inhibitor, poziotinib, for HER2 exon 20 mutations in lung cancer and mechanism of acquired resistance: An in vitro studyLung Cancer. 2018 Dec;126:72-79. doi: 10.1016/j.lungcan.2018.10.019. Epub 2018 Oct 17.
Ref 9 miR-17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells. J Drug Target. 2017 Feb;25(2):125-131. doi: 10.1080/1061186X.2016.1207647. Epub 2016 Sep 16.
Ref 10 MiR-497 downregulation contributes to the malignancy of pancreatic cancer and associates with a poor prognosis. Oncotarget. 2014 Aug 30;5(16):6983-93. doi: 10.18632/oncotarget.2184.
Ref 11 Exosome-mediated transfer of lncRNA RP11 838N2.4 promotes erlotinib resistance in non-small cell lung cancer. Int J Oncol. 2018 Aug;53(2):527-538. doi: 10.3892/ijo.2018.4412. Epub 2018 May 17.
Ref 12 Targeting EphA2 with miR-124 mediates Erlotinib resistance in K-RAS mutated pancreatic cancer. J Pharm Pharmacol. 2019 Feb;71(2):196-205. doi: 10.1111/jphp.12941. Epub 2019 Jan 2.
Ref 13 Targeting EGFR Activation to Overcome Gemcitabine Resistance in Cholangiocarcinoma. Anticancer Res. 2024 Dec;44(12):5393-5404.
Ref 14 Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011 Mar 23;3(75):75ra26. doi: 10.1126/scitranslmed.3002003.
Ref 15 Erlotinib in African Americans with advanced non-small cell lung cancer: a prospective randomized study with genetic and pharmacokinetic analyses. Clin Pharmacol Ther. 2014 Aug;96(2):182-91. doi: 10.1038/clpt.2014.93. Epub 2014 Apr 29.
Ref 16 Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014 Aug;11(8):473-81. doi: 10.1038/nrclinonc.2014.104. Epub 2014 Jul 1.
Ref 17 Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013 Aug;10(8):472-84. doi: 10.1038/nrclinonc.2013.110. Epub 2013 Jul 9.
Ref 18 Mechanism of Resistance and Novel Targets Mediating Resistance to EGFR and c-Met Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. PLoS One. 2015 Aug 24;10(8):e0136155. doi: 10.1371/journal.pone.0136155. eCollection 2015.
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Ref 20 EGFR exon 19 insertion EGFR-K745_E746insIPVAIK and others with rare XPVAIK amino-acid insertions: Preclinical and clinical characterization of the favorable therapeutic window to all classes of approved EGFR kinase inhibitors. Lung Cancer. 2023 Jul;181:107250.
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