Drug Information

Drug (ID: DG00137) and It's Reported Resistant Information
Name
Gefitinib
Synonyms
Gefitini; IRE; Iressa; Irressat; Gefitinib [USAN]; ZD 1839; ZD1839; Iressa (TN); Iressa(TM); ZD-1839; CU-00000000396-1; Gefitinib,Iressa, ZD1839; Gefitinib (JAN/USAN/INN); ZD-1839, Iressa, Gefitinib; N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)-4-quinazolinamide; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine; N-(3-Chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine; 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline; 6-(3-morpholinopropoxy)-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine
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Indication
In total 3 Indication(s)
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Approved
[1]
Head and neck cancer [ICD-11: 2D42]
Phase 3
[1]
Urethral cancer [ICD-11: 2C93]
Phase 2
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Lung cancer [ICD-11: 2C25]
[2]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
Esophageal cancer [ICD-11: 2B70]
[3]
Lung cancer [ICD-11: 2C25]
[4]
Target Epidermal growth factor receptor (EGFR) EGFR_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C22H24ClFN4O3
IsoSMILES
COC1=C(C=C2C(=C1)N=CN=C2NC3=CC(=C(C=C3)F)Cl)OCCCN4CCOCC4
InChI
1S/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)
InChIKey
XGALLCVXEZPNRQ-UHFFFAOYSA-N
PubChem CID
123631
ChEBI ID
CHEBI:49668
TTD Drug ID
D09XZB
VARIDT ID
DR00423
INTEDE ID
DR0764
DrugBank ID
DB00317
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
  DISM: Drug Inactivation by Structure Modification
  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
Esophageal cancer [ICD-11: 2B70]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell colony Activation hsa05200
Cell viability Activation hsa05200
miR129/BCL2 signaling pathway Regulation hsa05206
In Vitro Model TE-1 cells Esophagus Homo sapiens (Human) CVCL_1759
KYSE-450 cells Esophagus Homo sapiens (Human) CVCL_1353
TE6 cells Esophageal Homo sapiens (Human) CVCL_1765
TE8 cells Esophageal Homo sapiens (Human) CVCL_1766
TTn cells Esophageal Homo sapiens (Human) CVCL_3175
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; TUNEL assay
Mechanism Description Exosome-mediated transfer of PART1 promoted gefitinib resistance by competitively binding to miR-129 to facilitate Bcl-2 expression in ESCC cells.
Key Molecule: Prostate androgen-regulated transcript 1 (PART1) [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell colony Activation hsa05200
Cell viability Activation hsa05200
miR129/BCL2 signaling pathway Regulation hsa05206
In Vitro Model TE-1 cells Esophagus Homo sapiens (Human) CVCL_1759
KYSE-450 cells Esophagus Homo sapiens (Human) CVCL_1353
TE6 cells Esophageal Homo sapiens (Human) CVCL_1765
TE8 cells Esophageal Homo sapiens (Human) CVCL_1766
TTn cells Esophageal Homo sapiens (Human) CVCL_3175
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; TUNEL assay
Mechanism Description Exosome-mediated transfer of PART1 promoted gefitinib resistance by competitively binding to miR-129 to facilitate Bcl-2 expression in ESCC cells.
Key Molecule: hsa-mir-129 [3]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell colony Activation hsa05200
Cell viability Activation hsa05200
miR129/BCL2 signaling pathway Regulation hsa05206
In Vitro Model TE-1 cells Esophagus Homo sapiens (Human) CVCL_1759
KYSE-450 cells Esophagus Homo sapiens (Human) CVCL_1353
TE6 cells Esophageal Homo sapiens (Human) CVCL_1765
TE8 cells Esophageal Homo sapiens (Human) CVCL_1766
TTn cells Esophageal Homo sapiens (Human) CVCL_3175
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; TUNEL assay
Mechanism Description Exosome-mediated transfer of PART1 promoted gefitinib resistance by competitively binding to miR-129 to facilitate Bcl-2 expression in ESCC cells.
Key Molecule: Prostate androgen-regulated transcript 1 (PART1) [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell colony Activation hsa05200
Cell viability Activation hsa05200
miR129/BCL2 signaling pathway Regulation hsa05206
In Vitro Model TE-1 cells Esophagus Homo sapiens (Human) CVCL_1759
KYSE-450 cells Esophagus Homo sapiens (Human) CVCL_1353
TE6 cells Esophageal Homo sapiens (Human) CVCL_1765
TE8 cells Esophageal Homo sapiens (Human) CVCL_1766
TTn cells Esophageal Homo sapiens (Human) CVCL_3175
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 CCK8 assay; TUNEL assay
Mechanism Description Exosome-mediated transfer of PART1 promoted gefitinib resistance by competitively binding to miR-129 to facilitate Bcl-2 expression in ESCC cells.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-1 [5]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
PI3K/AKT/survivin signaling pathway Inhibition hsa04151
In Vitro Model TE-1 cells Esophagus Homo sapiens (Human) CVCL_1759
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Exogenous expression of miR 1 inhibited growth, arrested cell cycle in the G1 phase and increased apoptosis in ESCC cells, whereas it decreased PIk3CA protein expression levels. Furthermore, overexpression of miR 1 increased the sensitivity of ESCC cells to the anticancer drug, gefitinib.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: PI3-kinase alpha (PIK3CA) [5]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
PI3K/AKT/survivin signaling pathway Inhibition hsa04151
In Vitro Model TE-1 cells Esophagus Homo sapiens (Human) CVCL_1759
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Exogenous expression of miR 1 inhibited growth, arrested cell cycle in the G1 phase and increased apoptosis in ESCC cells, whereas it decreased PIk3CA protein expression levels. Furthermore, overexpression of miR 1 increased the sensitivity of ESCC cells to the anticancer drug, gefitinib.
Colorectal cancer [ICD-11: 2B91]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-147 [6]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Inhibition hsa04670
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		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-147 strikingly increased the sensitivity to EGFR inhibitor, gefitinib in cell with native resistance.
Liver cancer [ICD-11: 2C12]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [7]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
SNU182 cells Liver Homo sapiens (Human) CVCL_0090
SNU-739 cells Liver Homo sapiens (Human) CVCL_5088
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo luminescent cell viability assay
Mechanism Description miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-27b [7]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
SNU182 cells Liver Homo sapiens (Human) CVCL_0090
SNU-739 cells Liver Homo sapiens (Human) CVCL_5088
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 CellTiter-Glo luminescent cell viability assay
Mechanism Description miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cyclin-G1 (CCNG1) [7]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
SNU182 cells Liver Homo sapiens (Human) CVCL_0090
SNU-739 cells Liver Homo sapiens (Human) CVCL_5088
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo luminescent cell viability assay
Mechanism Description miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.
Lung cancer [ICD-11: 2C25]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [8]
Molecule Alteration Missense mutation
p.C797S
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [9], [10], [11]
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [2], [12], [13]
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [14], [15], [16]
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
Resistant Disease Lung squamous cell carcinoma [ICD-11: 2C25.3]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [17]
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [8]
Molecule Alteration Missense mutation
p.C797S+p.T790M
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [18]
Molecule Alteration Missense mutation
p.D761Y
 Molecule Info 
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [19]
Molecule Alteration Missense mutation
p.L747S
 Molecule Info 
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease 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) [19]
Molecule Alteration Missense mutation
p.D761Y
 Molecule Info 
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease 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) [19]
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease 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. 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) [20]
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease 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 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) [2]
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [2]
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-200a [1]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Activation hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description LncRNA MALAT1 promoted the proliferation and gefitinib resistance of lung cancer cells by sponging miR-200a, which regulates expression of ZEB1 in the A549 cells.
Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Activation hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description LncRNA MALAT1 promoted the proliferation and gefitinib resistance of lung cancer cells by sponging miR-200a, which regulates expression of ZEB1 in the A549 cells.
Key Molecule: MBNL1 antisense RNA 1 (MBNL1-AS1) [21]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
TGF-beta signaling pathway Inhibition hsa04350
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Colony formation assay; Flow cytometry assay
Mechanism Description LncRNA MBNL1-AS1 restoration could decelerate the occurrence and progression of NSCLC, thereby highlighting the functionality of LncRNA MBNL1-AS1 restoration as a sponge of miR-301b-3p to suppress the proliferation, invasion, drug resistance, and sphere formation of CSC cells in NSCLC via upregulation of TGFBR2.
Key Molecule: hsa-miR-301b-3p [21]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
TGF-beta signaling pathway Inhibition hsa04350
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Colony formation assay; Flow cytometry assay
Mechanism Description LncRNA MBNL1-AS1 restoration could decelerate the occurrence and progression of NSCLC, thereby highlighting the functionality of LncRNA MBNL1-AS1 restoration as a sponge of miR-301b-3p to suppress the proliferation, invasion, drug resistance, and sphere formation of CSC cells in NSCLC via upregulation of TGFBR2.
Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [22]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
SPC-A1 cells Lung Homo sapiens (Human) CVCL_6955
H1299 cells Lung Homo sapiens (Human) CVCL_0060
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; CCK8 assay; Colony formation assay; Flow cytometry assay
Mechanism Description MALAT1 could alter chemo-resistance (Cisplatin, Adriamycin, Gefitinib and Paclitaxel) of NSCLC cells by targeting miR-197-3p and regulating p120-ctn expression, which might assist in improvement of chemo-therapies for NSCLC.
Key Molecule: hsa-miR-197-3p [22]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
SPC-A1 cells Lung Homo sapiens (Human) CVCL_6955
H1299 cells Lung Homo sapiens (Human) CVCL_0060
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; CCK8 assay; Colony formation assay; Flow cytometry assay
Mechanism Description MALAT1 could alter chemo-resistance (Cisplatin, Adriamycin, Gefitinib and Paclitaxel) of NSCLC cells by targeting miR-197-3p and regulating p120-ctn expression, which might assist in improvement of chemo-therapies for NSCLC.
Key Molecule: hsa-miR-769-5p [23]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell viability 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		 qRT-PCR
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.
Key Molecule: Long non-protein coding RNA 460 (LINC00460) [23]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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		 qRT-PCR
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.
Key Molecule: hsa-miR-1183 [24]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease 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 [24]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease 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-181a [25]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/ERK signaling pathway Regulation hsa04010
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9GR cells Lung Homo sapiens (Human) CVCL_V337
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Down-regulation of GAS7 expression could antagonize gefitinib re-sensitivity in PC9GR mediated by knockdown of miR181a via AkT/ERk pathways and epithelial-to-mesenchymal transition markers.
Key Molecule: hsa-let-7b [26]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
A549/GR cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometric analysis
Mechanism Description Increased miR17-5p and miR92a expression and decreased let-7b expression can significantly induce proliferation and inhibit apoptosis of lung cancer cells, while reducing lung cancer cell sensitivity to Gefitinib.
Key Molecule: hsa-miR-17-5p [26]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
A549/GR cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometric analysis
Mechanism Description Increased miR17-5p and miR92a expression and decreased let-7b expression can significantly induce proliferation and inhibit apoptosis of lung cancer cells, while reducing lung cancer cell sensitivity to Gefitinib.
Key Molecule: hsa-mir-92a [26]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
A549/GR cells Lung Homo sapiens (Human) CVCL_0023
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometric analysis
Mechanism Description Increased miR17-5p and miR92a expression and decreased let-7b expression can significantly induce proliferation and inhibit apoptosis of lung cancer cells, while reducing lung cancer cell sensitivity to Gefitinib.
Key Molecule: MIR31 host gene (MIR31HG) [27]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation EGFR/PI3K/AKT signaling pathway Regulation hsa01521
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9R cells Lung Homo sapiens (Human) CVCL_D778
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Annexin V-FITC/PI double staining assay
Mechanism Description Increased MIR31HG LncRNA expression increases gefitinib resistance in non-small cell lung cancer cell lines through the EGFR/PI3k/AkT signaling pathway.
Key Molecule: Long non-protein coding RNA 665 (LINC00665) [28]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell colony Activation hsa05200
Cell invasion Activation hsa05200
Cell viability Activation hsa05200
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description LINC00665 Induces Acquired Resistance to Gefitinib through Recruiting EZH2 and Activating PI3k/AkT Pathway in NSCLC.
Key Molecule: hsa-mir-214 [29]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell viability Activation hsa05200
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-214 level was upregulated in gefitinib-resistant PC-9GR cells and their derived exosomes while anti-apoptotic protein of bcl-2 is uoregulated.
Key Molecule: hsa-mir-221 [30]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell viability Activation hsa05200
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-221 may inhibit apoptosis by down regulating the expression of Apaf-1, so as to induce the resistance of PC-9 cells to gefitinib.
Key Molecule: hsa-mir-138 [31]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-138 inhibit the protein level of EGFR and reverses gefitinib resistance in lung cancer cells.
Key Molecule: hsa-mir-873 [32]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell autophagy Activation hsa04140
Cell viability Activation hsa05200
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description The inhibition of miR-873 increased gefitinib resistance of NSCLC cells via the upregulation of GLI1.
Key Molecule: Small nucleolar RNA host gene 5 (SNHG5) [33]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
miR377/CASP1 signaling pathway Regulation hsa05206
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description SNHG5 overexpression sensitized gefitinib resistant LAD cells to gefitinib treatment; Overexpression of SNHG5 suppressed the expression of miR-377; Overexpression of miR-377 suppressed the expression of CASP1 in PC9 cells; knockdown of CASP1 in SNHG5-overexpressed PC9GR cells abolished their gefitinib resistance.
Key Molecule: hsa-miR-630 [34]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell viability Activation hsa05200
miR630/YAP1/ERK signaling pathway Regulation hsa05206
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9GR cells Lung Homo sapiens (Human) CVCL_V337
CL97 cells Lung Homo sapiens (Human) CVCL_N826
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description Low miR-630 and high YAP1 mRNA levels are associated with unfavorable response to TkI therapy in lung adenocarcinoma patients.
Key Molecule: hsa-mir-135a [35]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Activation hsa04670
Cell viability Activation hsa05200
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay; Transwell assay
Mechanism Description miR-135a promoted cell growth and metastasis and activated the PI3k/AkT signaling pathway via a RAC1-dependent manner.
Key Molecule: hsa-mir-26a [36]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Activation hsa05200
EGFR signaling pathway Activation hsa01521
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
SPC-A1 cells Lung Homo sapiens (Human) CVCL_6955
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NCI-H520 cells Lung Homo sapiens (Human) CVCL_1566
H2170 cells Lung Homo sapiens (Human) CVCL_1535
SW900 cells Lung Homo sapiens (Human) CVCL_1731
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-26a desensitizes non-small cell lung cancer cells to tyrosine kinase inhibitors by targeting and reducing the level of PTPN1.
Key Molecule: hsa-mir-21 [37]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/ERK signaling pathway Activation hsa04010
Cell apoptosis Inhibition hsa04210
Cell migration Inhibition hsa04670
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-21 was up-regulated concomitantly to down-regulation of Pten in pc-9/GR cells in comparison with pc-9 cells. Moreover, over-expression of miR-21 significantly decreased gefitinib sensitivity by down-regulating Pten expression and activating Akt and ERk pathways in pc-9 cells, while miR-21 knockdown dramatically restored gefitinib sensitivity of pc-9/GR cells by up-regulation of Pten expression and inactivation of AkT and ERk pathways, in vivo and in vitro.
Key Molecule: hsa-mir-21 [38]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9R cells Lung Homo sapiens (Human) CVCL_D778
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-21 overexpression is associated with the acquired resistance of EGFR-TkI in NSCLC, which might be caused by miR-21's function of activating PI3k/AkT pathway through inhibiting PTEN and PDCD4.
       Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: Hepatocyte growth factor receptor (MET) [39]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Epithelial mesenchymal transition signaling pathway Activation hsa01521
miR19a/c-Met signaling pathway Regulation hsa05206
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
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9GR cells Lung Homo sapiens (Human) CVCL_V337
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
Mechanism Description miR19a contributes to gefitinib resistance and epithelial mesenchymal transition in non-small cell lung cancer cells by targeting c-Met. Overexpression of miR19a decreased c-Met expression and re-sensitized gefitinib-resistant NSCLC cells in vitro and in vivo. Decreased miR19a expression may contribute to NSCLC cell metastasis by increasing cell mobility and migration and promoting EMT.
Key Molecule: hsa-mir-19a [39]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Epithelial mesenchymal transition signaling pathway Inhibition hsa01521
miR19a/c-Met signaling pathway Regulation hsa05206
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
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9GR cells Lung Homo sapiens (Human) CVCL_V337
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR19a contributes to gefitinib resistance and epithelial mesenchymal transition in non-small cell lung cancer cells by targeting c-Met. Overexpression of miR19a decreased c-Met expression and re-sensitized gefitinib-resistant NSCLC cells in vitro and in vivo. Decreased miR19a expression may contribute to NSCLC cell metastasis by increasing cell mobility and migration and promoting EMT.
Key Molecule: Gem-associated protein 2 (SIP1) [40]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Beta-catenin signaling pathway Activation hsa04520
Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
In Vitro Model 95D cells Lung Homo sapiens (Human) CVCL_7110
95C cells Lung Homo sapiens (Human) CVCL_7109
YTMLC-90 cells Lung Homo sapiens (Human) CVCL_6959
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 EdU assay
Mechanism Description HOTAIR also regulates non-small-cell lung cancer proliferation, migration and invasion through epithelial-mesenchymal transition and the beta-catenin pathway.
Key Molecule: HOX transcript antisense RNA (HOTAIR) [40]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Beta-catenin signaling pathway Activation hsa04520
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
Epithelial mesenchymal transition signaling pathway Activation hsa01521
In Vitro Model 95D cells Lung Homo sapiens (Human) CVCL_7110
95C cells Lung Homo sapiens (Human) CVCL_7109
YTMLC-90 cells Lung Homo sapiens (Human) CVCL_6959
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 EdU assay
Mechanism Description HOTAIR also regulates non-small-cell lung cancer proliferation, migration and invasion through epithelial-mesenchymal transition and the beta-catenin pathway.
Key Molecule: Membrane-associated guanylate kinase inverted 2 (MAGI2) [4]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model PC3 cells Prostate Homo sapiens (Human) CVCL_0035
A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC-14 cells Lung Homo sapiens (Human) CVCL_1640
LC-2/ad cells Lung Homo sapiens (Human) CVCL_1373
RERF-LCkJ cells Lung Homo sapiens (Human) CVCL_1654
ABC-1 cells Lung Homo sapiens (Human) CVCL_1066
RERF-LCMS cells Lung Homo sapiens (Human) CVCL_1655
Experiment for
Molecule Alteration		 Western blottling analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-134/487b/655 cluster contributed to the TGF-beta1-induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, in which suppression subsequently caused loss of PTEN stability in lung cancer cells.
Key Molecule: hsa-mir-134 [4]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model PC3 cells Prostate Homo sapiens (Human) CVCL_0035
A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC-14 cells Lung Homo sapiens (Human) CVCL_1640
LC-2/ad cells Lung Homo sapiens (Human) CVCL_1373
RERF-LCkJ cells Lung Homo sapiens (Human) CVCL_1654
ABC-1 cells Lung Homo sapiens (Human) CVCL_1066
RERF-LCMS cells Lung Homo sapiens (Human) CVCL_1655
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-134/487b/655 cluster contributed to the TGF-beta1-induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, in which suppression subsequently caused loss of PTEN stability in lung cancer cells.
Key Molecule: hsa-mir-487b [4]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model PC3 cells Prostate Homo sapiens (Human) CVCL_0035
A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC-14 cells Lung Homo sapiens (Human) CVCL_1640
LC-2/ad cells Lung Homo sapiens (Human) CVCL_1373
RERF-LCkJ cells Lung Homo sapiens (Human) CVCL_1654
ABC-1 cells Lung Homo sapiens (Human) CVCL_1066
RERF-LCMS cells Lung Homo sapiens (Human) CVCL_1655
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-134/487b/655 cluster contributed to the TGF-beta1-induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, in which suppression subsequently caused loss of PTEN stability in lung cancer cells.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: TGF-beta receptor type II (TGFBR2) [21]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
TGF-beta signaling pathway Inhibition hsa04350
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Colony formation assay; Flow cytometry assay
Mechanism Description LncRNA MBNL1-AS1 restoration could decelerate the occurrence and progression of NSCLC, thereby highlighting the functionality of LncRNA MBNL1-AS1 restoration as a sponge of miR-301b-3p to suppress the proliferation, invasion, drug resistance, and sphere formation of CSC cells in NSCLC via upregulation of TGFBR2.
Key Molecule: Catenin delta-1 (CTNND1) [22]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
SPC-A1 cells Lung Homo sapiens (Human) CVCL_6955
H1299 cells Lung Homo sapiens (Human) CVCL_0060
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 MTT assay; CCK8 assay; Colony formation assay; Flow cytometry assay
Mechanism Description MALAT1 could alter chemo-resistance (Cisplatin, Adriamycin, Gefitinib and Paclitaxel) of NSCLC cells by targeting miR-197-3p and regulating p120-ctn expression, which might assist in improvement of chemo-therapies for NSCLC.
Key Molecule: Epidermal growth factor receptor (EGFR) [23]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
Key Molecule: phosphoinositide-3-dependent protein kinase 1 (PDPK1) [24]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease 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		 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: Growth arrest-specific protein 7 (GAS7) [25]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/ERK signaling pathway Regulation hsa04010
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9GR cells Lung Homo sapiens (Human) CVCL_V337
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Down-regulation of GAS7 expression could antagonize gefitinib re-sensitivity in PC9GR mediated by knockdown of miR181a via AkT/ERk pathways and epithelial-to-mesenchymal transition markers.
Key Molecule: RAC serine/threonine-protein kinase (AKT) [28]
Molecule Alteration Phosphorylation
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell viability Activation hsa05200
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description LINC00665 Induces Acquired Resistance to Gefitinib through Recruiting EZH2 and Activating PI3k/AkT Pathway in NSCLC.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [29]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell viability Activation hsa05200
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Flow cytometry assay
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-214 level was upregulated in gefitinib-resistant PC-9GR cells and their derived exosomes while anti-apoptotic protein of bcl-2 is uoregulated.
Key Molecule: Apoptotic protease-activating factor 1 (APAF1) [30]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell viability Activation hsa05200
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-221 may inhibit apoptosis by down regulating the expression of Apaf-1, so as to induce the resistance of PC-9 cells to gefitinib.
Key Molecule: Epidermal growth factor receptor (EGFR) [31]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
Key Molecule: Zinc finger protein GLI1 (GLI1) [32]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell viability Activation hsa05200
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description The inhibition of miR-873 increased gefitinib resistance of NSCLC cells via the upregulation of GLI1.
Key Molecule: Caspase-1 (CASP1) [33]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
miR377/CASP1 signaling pathway Regulation hsa05206
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		 CCK8 assay; Flow cytometry assay
Mechanism Description SNHG5 overexpression sensitized gefitinib resistant LAD cells to gefitinib treatment; Overexpression of SNHG5 suppressed the expression of miR-377; Overexpression of miR-377 suppressed the expression of CASP1 in PC9 cells; knockdown of CASP1 in SNHG5-overexpressed PC9GR cells abolished their gefitinib resistance.
Key Molecule: Transcriptional coactivator YAP1 (YAP1) [34]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell viability Activation hsa05200
miR630/YAP1/ERK signaling pathway Regulation hsa05206
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9GR cells Lung Homo sapiens (Human) CVCL_V337
CL97 cells Lung Homo sapiens (Human) CVCL_N826
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description Low miR-630 and high YAP1 mRNA levels are associated with unfavorable response to TkI therapy in lung adenocarcinoma patients.
Key Molecule: Ras-related C3 botulinum toxin substrate 1 (RAC1) [35]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell viability Activation hsa05200
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay; Transwell assay
Mechanism Description miR-135a promoted cell growth and metastasis and activated the PI3k/AkT signaling pathway via a RAC1-dependent manner.
Key Molecule: Tyrosine-protein phosphatase non-receptor type 13 (PTPN13) [36]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Activation hsa05200
EGFR signaling pathway Activation hsa01521
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
SPC-A1 cells Lung Homo sapiens (Human) CVCL_6955
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NCI-H520 cells Lung Homo sapiens (Human) CVCL_1566
H2170 cells Lung Homo sapiens (Human) CVCL_1535
SW900 cells Lung Homo sapiens (Human) CVCL_1731
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-26a desensitizes non-small cell lung cancer cells to tyrosine kinase inhibitors by targeting and reducing the level of PTPN1.
Key Molecule: Phosphatase and tensin homolog (PTEN) [37]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/ERK signaling pathway Activation hsa04010
Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-21 was up-regulated concomitantly to down-regulation of Pten in pc-9/GR cells in comparison with pc-9 cells. Moreover, over-expression of miR-21 significantly decreased gefitinib sensitivity by down-regulating Pten expression and activating Akt and ERk pathways in pc-9 cells, while miR-21 knockdown dramatically restored gefitinib sensitivity of pc-9/GR cells by up-regulation of Pten expression and inactivation of AkT and ERk pathways, in vivo and in vitro.
Key Molecule: Programmed cell death protein 4 (PDCD4) [38]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9R cells Lung Homo sapiens (Human) CVCL_D778
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-21 overexpression is associated with the acquired resistance of EGFR-TkI in NSCLC, which might be caused by miR-21's function of activating PI3k/AkT pathway through inhibiting PTEN and PDCD4.
Key Molecule: Phosphatase and tensin homolog (PTEN) [38]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9R cells Lung Homo sapiens (Human) CVCL_D778
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-21 overexpression is associated with the acquired resistance of EGFR-TkI in NSCLC, which might be caused by miR-21's function of activating PI3k/AkT pathway through inhibiting PTEN and PDCD4.
Key Molecule: Phosphatase and tensin homolog (PTEN) [8]
Molecule Alteration Structural variation
Copy number loss
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
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.
Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [8]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
Key Molecule: Phosphatase and tensin homolog (PTEN) [8]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
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.
Key Molecule: Cellular tumor antigen p53 (TP53) [41]
Molecule Alteration Missense mutation
p.Y163C
 Molecule Info 
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AXLK signaling pathway Activation hsa01521
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.
Key Molecule: DNA-binding factor KBF1 (p105) (NFKB1) [41]
Molecule Alteration Missense mutation
p.G489V
 Molecule Info 
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Angiogenic potential Inhibition hsa04370
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [41]
Molecule Alteration Missense mutation
p.T790M
 Molecule Info 
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
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.
Key Molecule: Hepatocyte growth factor receptor (MET) [17]
Molecule Alteration Structural variation
Amplification
 Molecule Info 
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
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.
Key Molecule: PI3-kinase alpha (PIK3CA) [17]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease Info 
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.
Key Molecule: PI3-kinase alpha (PIK3CA) [19]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease 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) [19]
Molecule Alteration Structural variation
Copy number gain
 Molecule Info 
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease 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) [19]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease 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) [19]
Molecule Alteration Structural variation
Copy number gain
 Molecule Info 
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease 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) [19]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease 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: DNA-binding factor KBF1 (p105) (NFKB1) [41]
Molecule Alteration Missense mutation
p.G489V
 Molecule Info 
Resistant Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
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.
Key Molecule: PI3-kinase alpha (PIK3CA) [20]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Disease EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
 Disease 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.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [8]
Molecule Alteration Missense mutation
p.L858R
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [8]
Molecule Alteration Frameshift mutation
p.E746-A750del
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-135a [42]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
JAKT/STAT signaling pathway Inhibition hsa04630
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
H157 cells Lung Homo sapiens (Human) CVCL_2458
H4006 cells Lung Homo sapiens (Human) N.A.
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR135 acted as a tumor promoter, and its suppression could improve sensitivity to gefitinib by targeting TRIM16 and inhibition of the JAk/STAT pathway.
Key Molecule: hsa-mir-30e [43]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
PC9 cells Lung Homo sapiens (Human) CVCL_B260
HCC827/GR cells Lung Homo sapiens (Human) CVCL_V620
PC9G cells Lung Homo sapiens (Human) CVCL_V337
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR30e overexpression inPC9G cells resulted in reduced cell proliferation and migration,reversing drug resistance to gefitinib, miR30e directly targeted HOXA1 in lung cancer cells.
Key Molecule: hsa-mir-200c [44]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Inhibition hsa04670
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9-ZD cells Lung Homo sapiens (Human) CVCL_V337
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Annexin-V/PI assay; Wound healing assay
Mechanism Description miR200c enhances sensitivity of drug-resistant non-small cell lung cancer to gefitinib by suppression of PI3k/Akt signaling pathway and inhibites cell migration via targeting ZEB1.
Key Molecule: hsa-mir-124 [45]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Annexin V-FITC Apoptosis assay
Mechanism Description miR124 decreased SNAI2 and STAT3 expression by directly targeting their 3'UTRs, miR124 contributes to gefitinib and EMT by directly targeting SNAI2 and STAT3. Over-expression of miR124 re-sensitized gefitinib-resistant cell lines to gefitinib.
Key Molecule: hsa-miR-30a-5p [46]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease 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-128a [47]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation c-Met/PI3K/AKT signaling pathway Inhibition hsa01521
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR128 reverses the gefitinib resistance of the lung cancer stem cells by inhibiting the c-met/PI3k/AkT pathway. The miR128/c-met pathway enhances the gefitinib sensitivity of the lung cancer stem cells by suppressing the PI3k/AkT pathway.
Key Molecule: hsa-miR-506-3p [48]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description The elevated sensitivity of PC 9GR cells to gefitinib following transfection with the miR 506 3p mimic was counteracted by the overexpression of YAP1.
Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [49]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell colony Inhibition hsa05200
Cell viability Inhibition hsa05200
STAT3 signaling pathway Inhibition hsa04550
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
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 PPI might down-regulate MALAT1 expression and inactivate STAT3 signaling pathway and could serve a promising therapeutic agent for gefitinib-resistant NSCLC.
Key Molecule: hsa-miR-124-3p [50]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
In Vitro Model SPC-A1 cells Lung Homo sapiens (Human) CVCL_6955
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description USP14 is a direct target of hsa-miR-124a, and that hsa-miR-124a inhibits stemness and enhances the gefitinib sensitivity of NSCLC cells by targeting USP14.
Key Molecule: Small nucleolar RNA host gene 5 (SNHG5) [33]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
miR377/CASP1 signaling pathway Regulation hsa05206
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description SNHG5 overexpression sensitized gefitinib resistant LAD cells to gefitinib treatment; Overexpression of SNHG5 suppressed the expression of miR-377; Overexpression of miR-377 suppressed the expression of CASP1 in PC9 cells; knockdown of CASP1 in SNHG5-overexpressed PC9GR cells abolished their gefitinib resistance.
Key Molecule: hsa-mir-377 [33]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
miR377/CASP1 signaling pathway Regulation hsa05206
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description SNHG5 overexpression sensitized gefitinib resistant LAD cells to gefitinib treatment; Overexpression of SNHG5 suppressed the expression of miR-377; Overexpression of miR-377 suppressed the expression of CASP1 in PC9 cells; knockdown of CASP1 in SNHG5-overexpressed PC9GR cells abolished their gefitinib resistance.
Key Molecule: hsa-mir-200a [51]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
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.
Key Molecule: Growth arrest specific 5 (GAS5) [52]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
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		 qRT-PCR
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.
Key Molecule: hsa-mir-7 [53]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
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		 qPCR
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.
Key Molecule: hsa-mir-34 [54]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
HGF/ MET signaling pathway Inhibition hsa04151
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
MRC-5 cells Lung Homo sapiens (Human) CVCL_0440
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 WST-8 assay; Flow cytometry assay
Mechanism Description In the HGF-induced gefitinib-resistant cell model, the exposure of miR-34a plus gefitinib efficiently inhibited the phosphorylation of MET, EGFR, Akt and ERk, and induced cell death, and apoptosis. In the presence of HGF, although EGFR was successfully inhibited by gefitinib monotherapy, the downstream pathways (PI3k/Akt and ERk pathway) were nevertheless activated by MET activation. Through addition of miR-34a to these cells, both MET and EGFR were successfully inhibited and subsequently the downstream pathways were blocked. However, the inhibitory effect of miR-34a on of MET and downstream pathways was lower than that for the MET-TkI. These results suggested that the combination of miR-34a and gefitinib was able to partially inhibit downstream pathways activation though inhibition of MET and EGFR activation in EGFR mutant NSCLC cells, though this effect was lower than what has been observed for MET-TkI.
Key Molecule: hsa-mir-130a [55]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9GR cells Lung Homo sapiens (Human) CVCL_V337
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Expression of Met has been associated with both primary and acquired resistance to gefitinib, miR-130a expression was negatively correlated with that of Met. Over-expression of miR-130a increased cell apoptosis and inhibited proliferation of NSCLC cells treated with gefitinib, whereas lowering the expression of miR-130a decreased cell apoptosis and promoted cell proliferation after treatment with gefitinib in both gefitinib-sensitive and -resistant NSCLC cell lines.
Key Molecule: hsa-miR-138-5p [56]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description There is an inverse correlation between the expression of miR-138-5p and GPR124 in lung adenocarcinoma specimens. Down-regulation of miR-138-5p contributes to gefitinib resistance and that restoration of miR-138-5p or inhibition GPR124 might serve as potential therapeutic approach for overcoming NSCLC gefitinib resistance.
Key Molecule: hsa-mir-147 [6]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
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 miR-147 strikingly increased the sensitivity to EGFR inhibitor, gefitinib in cell with native resistance.
Key Molecule: hsa-let-7c [57]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation ERK signaling pathway Inhibition hsa04210
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description The upregulation of let-7c was associated with the increased gefitinib sensitivity of H1975 cells, and that this effect was mediated by repression of the RAS oncogene and inactivation of the phosphoinositide 3-kinase (PI3k) /AkT and mitogen-activated extracellular signal-regulated kinase (MEk) /extracellular signal-regulated kinase (ERk) signaling pathways.
Key Molecule: hsa-miR-133b [58]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
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		 qRT-PCR
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.
Key Molecule: hsa-mir-214 [59]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PTEN/AKT signaling pathway Activation hsa05235
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
NCI-HCC827 cells Lung Homo sapiens (Human) CVCL_2063
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The knockdown of miR-214 resulted in not only PTEN un-regulation, but also the inactivation of p-AkT. This evidence indicated that miR-214 could regulate PTEN/AkT signaling pathway in EGFR mutant NSCLC cells. Furthermore, the knockdown of miR-214 re-sensitized HCC827/GR to gefitinib. Taken together, these evidences suggested that miR-214 may regulate the acquired resistance to gefinib in EGFR mutant cell lines by targeting PTEN/AkT signaling pathway.
       Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: hnRNP A2/B1 (HNRNPA2B1) [60]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
HCC4006 cells Lung Homo sapiens (Human) CVCL_1269
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; TUNEL assay
Mechanism Description Knockdown of H19 by siRNA transfection can significantly reduce the expression of N-cadherin, as well as increase E-cadherin and vimentin level, which improved tamoxifen sensitivity in tamoxifen-resistant breast cancer cells.
Key Molecule: H19, imprinted maternally expressed transcript (H19) [60]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
HCC4006 cells Lung Homo sapiens (Human) CVCL_1269
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; TUNEL assay
Mechanism Description Knockdown of H19 by siRNA transfection can significantly reduce the expression of N-cadherin, as well as increase E-cadherin and vimentin level, which improved tamoxifen sensitivity in tamoxifen-resistant breast cancer cells.
Key Molecule: Centromere protein R (CENPR) [61]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell colony Inhibition hsa05200
Cell proliferation Inhibition hsa05200
Cell viability Inhibition hsa05200
FAKT/ERK signaling pathway Inhibition hsa04210
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
H292 cells Lung Homo sapiens (Human) CVCL_0455
A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
PC9 cells Lung Homo sapiens (Human) CVCL_B260
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; EdU incorporation assay; Flow cytometry assay; Transwell assay
Mechanism Description Epigenetic silencing of miR-483-3p promotes acquired gefitinib resistance and EMT in EGFR-mutant NSCLC by targeting integrin beta3.
Key Molecule: hsa-miR-483-3p [61]
Molecule Alteration Demethylation
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease 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
Cell viability Inhibition hsa05200
FAKT/ERK signaling pathway Inhibition hsa04210
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
H292 cells Lung Homo sapiens (Human) CVCL_0455
A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
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; EdU incorporation assay; Flow cytometry assay; Transwell assay
Mechanism Description Epigenetic silencing of miR-483-3p promotes acquired gefitinib resistance and EMT in EGFR-mutant NSCLC by targeting integrin beta3.
Key Molecule: hsa-mir-200c [62]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
MEK/ERK signaling pathway Regulation hsa04010
PI3K/AKT signaling pathway Regulation hsa04151
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
PC9 cells Lung Homo sapiens (Human) CVCL_B260
H23 cells Lung Homo sapiens (Human) CVCL_1547
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Ectopic expression of miR-200c resulted in partial restoration of gefitinib sensitivity in NSCLC cells with ZEB1 downrerulating.
Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [62]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
MEK/ERK signaling pathway Regulation hsa04010
PI3K/AKT signaling pathway Regulation hsa04151
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
PC9 cells Lung Homo sapiens (Human) CVCL_B260
H23 cells Lung Homo sapiens (Human) CVCL_1547
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Ectopic expression of miR-200c resulted in partial restoration of gefitinib sensitivity in NSCLC cells with ZEB1 downrerulating.
Key Molecule: G2/mitotic-specific cyclin-B1 (CCNB1) [63]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
Calu1 cells Lung Homo sapiens (Human) CVCL_0608
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay; Flow cytometry assay
Mechanism Description miR-374a and miR-548b modulated by Axl have essential roles in cell cycle arrest, gefitinib-induced apoptosis, epithelial-to-mesenchymal transition, migration and tumorigenesis of gefitinib-resistant lung cancer cells in vitro and in vivo by targeting Wnt5a and CCNB1 genes, respectively. Of clinical significance, high expression of Axl and miR-374a and low expression of miR-548b are associated with poor disease-free survival postoperatively. These findings indicate that the modulation of specific miRNAs may provide a therapeutic target to treat or reverse gefitinib resistance in NSCLC with high expression of Axl in the future. Overexpression of Wnt5a in HCC827-Gef cells partially restored the cell sensitivity to gefitinib (Wnt5a in HCC827-Gef cells partially restored the cell sensitivity to gefitinib.
Key Molecule: hsa-mir-374a [63]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
Calu1 cells Lung Homo sapiens (Human) CVCL_0608
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 MTS assay; Flow cytometry assay
Mechanism Description miR-374a and miR-548b modulated by Axl have essential roles in cell cycle arrest, gefitinib-induced apoptosis, epithelial-to-mesenchymal transition, migration and tumorigenesis of gefitinib-resistant lung cancer cells in vitro and in vivo by targeting Wnt5a and CCNB1 genes, respectively. Of clinical significance, high expression of Axl and miR-374a and low expression of miR-548b are associated with poor disease-free survival postoperatively. These findings indicate that the modulation of specific miRNAs may provide a therapeutic target to treat or reverse gefitinib resistance in NSCLC with high expression of Axl in the future. Overexpression of Wnt5a in HCC827-Gef cells partially restored the cell sensitivity to gefitinib (Wnt5a in HCC827-Gef cells partially restored the cell sensitivity to gefitinib.
Key Molecule: hsa-mir-548b [63]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
Calu1 cells Lung Homo sapiens (Human) CVCL_0608
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 MTS assay; Flow cytometry assay
Mechanism Description miR-374a and miR-548b modulated by Axl have essential roles in cell cycle arrest, gefitinib-induced apoptosis, epithelial-to-mesenchymal transition, migration and tumorigenesis of gefitinib-resistant lung cancer cells in vitro and in vivo by targeting Wnt5a and CCNB1 genes, respectively. Of clinical significance, high expression of Axl and miR-374a and low expression of miR-548b are associated with poor disease-free survival postoperatively. These findings indicate that the modulation of specific miRNAs may provide a therapeutic target to treat or reverse gefitinib resistance in NSCLC with high expression of Axl in the future. Overexpression of Wnt5a in HCC827-Gef cells partially restored the cell sensitivity to gefitinib (Wnt5a in HCC827-Gef cells partially restored the cell sensitivity to gefitinib.
Key Molecule: Protein Wnt-5a (WNT5A) [63]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
Calu1 cells Lung Homo sapiens (Human) CVCL_0608
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay; Flow cytometry assay
Mechanism Description miR-374a and miR-548b modulated by Axl have essential roles in cell cycle arrest, gefitinib-induced apoptosis, epithelial-to-mesenchymal transition, migration and tumorigenesis of gefitinib-resistant lung cancer cells in vitro and in vivo by targeting Wnt5a and CCNB1 genes, respectively. Of clinical significance, high expression of Axl and miR-374a and low expression of miR-548b are associated with poor disease-free survival postoperatively. These findings indicate that the modulation of specific miRNAs may provide a therapeutic target to treat or reverse gefitinib resistance in NSCLC with high expression of Axl in the future. Overexpression of Wnt5a in HCC827-Gef cells partially restored the cell sensitivity to gefitinib (Wnt5a in HCC827-Gef cells partially restored the cell sensitivity to gefitinib.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Tripartite motif-containing protein 16 (TRIM16) [42]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease 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 viability Inhibition hsa05200
JAKT/STAT signaling pathway Inhibition hsa04630
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
H157 cells Lung Homo sapiens (Human) CVCL_2458
H4006 cells Lung Homo sapiens (Human) N.A.
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
Experiment for
Molecule Alteration		 Dual-Luciferase activity assay; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR135 acted as a tumor promoter, and its suppression could improve sensitivity to gefitinib by targeting TRIM16 and inhibition of the JAk/STAT pathway.
Key Molecule: Homeobox protein Hox-A1 (HOXA1) [43]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
PC9 cells Lung Homo sapiens (Human) CVCL_B260
HCC827/GR cells Lung Homo sapiens (Human) CVCL_V620
PC9G cells Lung Homo sapiens (Human) CVCL_V337
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR30e overexpression inPC9G cells resulted in reduced cell proliferation and migration,reversing drug resistance to gefitinib, miR30e directly targeted HOXA1 in lung cancer cells.
Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [44]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Inhibition hsa04670
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9-ZD cells Lung Homo sapiens (Human) CVCL_V337
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Annexin-V/PI assay; Wound healing assay
Mechanism Description miR200c enhances sensitivity of drug-resistant non-small cell lung cancer to gefitinib by suppression of PI3k/Akt signaling pathway and inhibites cell migration via targeting ZEB1.
Key Molecule: Zinc finger protein SNAI2 (SNAI2) [45]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
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; Luciferase Assay
Experiment for
Drug Resistance		 CCK8 assay; Annexin V-FITC Apoptosis assay
Mechanism Description miR124 decreased SNAI2 and STAT3 expression by directly targeting their 3'UTRs, miR124 contributes to gefitinib and EMT by directly targeting S.I2 and STAT3. Over-expression of miR124 re-sensitized gefitinib-resistant cell lines to gefitinib.
Key Molecule: Signal transducer activator transcription 3 (STAT3) [45]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
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; Luciferase Assay
Experiment for
Drug Resistance		 CCK8 assay; Annexin V-FITC Apoptosis assay
Mechanism Description miR124 decreased SNAI2 and STAT3 expression by directly targeting their 3'UTRs, miR124 contributes to gefitinib and EMT by directly targeting SNAI2 and STAT3. Over-expression of miR124 re-sensitized gefitinib-resistant cell lines to gefitinib.
Key Molecule: Hepatocyte growth factor receptor (MET) [47]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation c-Met/PI3K/AKT signaling pathway Inhibition hsa01521
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR128 reverses the gefitinib resistance of the lung cancer stem cells by inhibiting the c-met/PI3k/AkT pathway. The miR128/c-met pathway enhances the gefitinib sensitivity of the lung cancer stem cells by suppressing the PI3k/AkT pathway.
Key Molecule: Transcriptional coactivator YAP1 (YAP1) [48]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description The elevated sensitivity of PC 9GR cells to gefitinib following transfection with the miR 506 3p mimic was counteracted by the overexpression of YAP1.
Key Molecule: Signal transducer activator transcription 3 (STAT3) [49]
Molecule Alteration Phosphorylation
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell colony Inhibition hsa05200
Cell viability Inhibition hsa05200
STAT3 signaling pathway Inhibition hsa04550
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
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 PPI might down-regulate MALAT1 expression and inactivate STAT3 signaling pathway and could serve a promising therapeutic agent for gefitinib-resistant NSCLC.
Key Molecule: Ubiquitin carboxyl-terminal hydrolase 14 (USP14) [50]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
In Vitro Model SPC-A1 cells Lung Homo sapiens (Human) CVCL_6955
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description USP14 is a direct target of hsa-miR-124a, and that hsa-miR-124a inhibits stemness and enhances the gefitinib sensitivity of NSCLC cells by targeting USP14.
Key Molecule: Caspase-1 (CASP1) [33]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
miR377/CASP1 signaling pathway Regulation hsa05206
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		 CCK8 assay; Flow cytometry assay
Mechanism Description SNHG5 overexpression sensitized gefitinib resistant LAD cells to gefitinib treatment; Overexpression of SNHG5 suppressed the expression of miR-377; Overexpression of miR-377 suppressed the expression of CASP1 in PC9 cells; knockdown of CASP1 in SNHG5-overexpressed PC9GR cells abolished their gefitinib resistance.
Key Molecule: Hepatocyte growth factor receptor (MET) [51]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [51]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [52]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
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.
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [52]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
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.
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [52]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
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.
Key Molecule: Epidermal growth factor receptor (EGFR) [53]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
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.
Key Molecule: Hepatocyte growth factor receptor (MET) [54]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
HGF/ MET signaling pathway Inhibition hsa04151
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
MRC-5 cells Lung Homo sapiens (Human) CVCL_0440
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 WST-8 assay; Flow cytometry assay
Mechanism Description In the HGF-induced gefitinib-resistant cell model, the exposure of miR-34a plus gefitinib efficiently inhibited the phosphorylation of MET, EGFR, Akt and ERk, and induced cell death, and apoptosis. In the presence of HGF, although EGFR was successfully inhibited by gefitinib monotherapy, the downstream pathways (PI3k/Akt and ERk pathway) were nevertheless activated by MET activation. Through addition of miR-34a to these cells, both MET and EGFR were successfully inhibited and subsequently the downstream pathways were blocked. However, the inhibitory effect of miR-34a on of MET and downstream pathways was lower than that for the MET-TkI. These results suggested that the combination of miR-34a and gefitinib was able to partially inhibit downstream pathways activation though inhibition of MET and EGFR activation in EGFR mutant NSCLC cells, though this effect was lower than what has been observed for MET-TkI.
Key Molecule: Hepatocyte growth factor receptor (MET) [55]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
A549 cells Lung Homo sapiens (Human) CVCL_0023
PC9GR cells Lung Homo sapiens (Human) CVCL_V337
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Expression of Met has been associated with both primary and acquired resistance to gefitinib, miR-130a expression was negatively correlated with that of Met. Over-expression of miR-130a increased cell apoptosis and inhibited proliferation of NSCLC cells treated with gefitinib, whereas lowering the expression of miR-130a decreased cell apoptosis and promoted cell proliferation after treatment with gefitinib in both gefitinib-sensitive and -resistant NSCLC cell lines.
Key Molecule: Adhesion G protein-coupled receptor A2 (ADGRA2) [56]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model PC9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description There is an inverse correlation between the expression of miR-138-5p and GPR124 in lung adenocarcinoma specimens. Down-regulation of miR-138-5p contributes to gefitinib resistance and that restoration of miR-138-5p or inhibition GPR124 might serve as potential therapeutic approach for overcoming NSCLC gefitinib resistance.
Key Molecule: Epidermal growth factor receptor (EGFR) [58]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
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 blotting 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.
Key Molecule: Phosphatase and tensin homolog (PTEN) [59]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PTEN/AKT signaling pathway Activation hsa05235
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
NCI-HCC827 cells Lung Homo sapiens (Human) CVCL_2063
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The knockdown of miR-214 resulted in not only PTEN un-regulation, but also the inactivation of p-AkT. This evidence indicated that miR-214 could regulate PTEN/AkT signaling pathway in EGFR mutant NSCLC cells. Furthermore, the knockdown of miR-214 re-sensitized HCC827/GR to gefitinib. Taken together, these evidences suggested that miR-214 may regulate the acquired resistance to gefinib in EGFR mutant cell lines by targeting PTEN/AkT signaling pathway.
Breast cancer [ICD-11: 2C60]
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-205 [64]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell growth Inhibition hsa05200
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 RT-PCR; Northern blotting analysis
Experiment for
Drug Resistance		 Fluorescence-activated cell sorting assay
Mechanism Description The activation of the PI3k/Akt survival pathway, so critically important in tumorigenesis, is for the most part driven through phosphorylation of the kinase-inactive member HER3. miR-205, negatively regulating HER3, is able to inhibit breast cancer cell proliferation and improves the response to specific targeted therapies. The reintroduction of miR-205 in SkBr3 cells inhibits their clonogenic potential and increases the responsiveness to tyrosine-kinase inhibitors Gefitinib and Lapatinib, abrogating the HER3-mediated resistance and restoring a potent proapoptotic activity.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Receptor tyrosine-protein kinase erbB-3 (ERBB3) [64]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell growth Inhibition hsa05200
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 Luciferase target assay
Experiment for
Drug Resistance		 Fluorescence-activated cell sorting assay
Mechanism Description The activation of the PI3k/Akt survival pathway, so critically important in tumorigenesis, is for the most part driven through phosphorylation of the kinase-inactive member HER3. miR-205, negatively regulating HER3, is able to inhibit breast cancer cell proliferation and improves the response to specific targeted therapies. The reintroduction of miR-205 in SkBr3 cells inhibits their clonogenic potential and increases the responsiveness to tyrosine-kinase inhibitors Gefitinib and Lapatinib, abrogating the HER3-mediated resistance and restoring a potent proapoptotic activity.
Kidney cancer [ICD-11: 2C90]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [7]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Kidney cancer [ICD-11: 2C90.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
In Vitro Model 769-P cells Kidney Homo sapiens (Human) CVCL_1050
786-O cells Kidney Homo sapiens (Human) CVCL_1051
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo luminescent cell viability assay
Mechanism Description miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-27b [7]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Kidney cancer [ICD-11: 2C90.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
In Vitro Model 769-P cells Kidney Homo sapiens (Human) CVCL_1050
786-O cells Kidney Homo sapiens (Human) CVCL_1051
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 CellTiter-Glo luminescent cell viability assay
Mechanism Description miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cyclin-G1 (CCNG1) [7]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Kidney cancer [ICD-11: 2C90.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
In Vitro Model 769-P cells Kidney Homo sapiens (Human) CVCL_1050
786-O cells Kidney Homo sapiens (Human) CVCL_1051
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo luminescent cell viability assay
Mechanism Description miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.
References
Ref 1 LncRNA MALAT1 Promotes Lung Cancer Proliferation and Gefitinib Resistance by Acting as a miR-200a Sponge. Arch Bronconeumol (Engl Ed). 2019 Dec;55(12):627-633. doi: 10.1016/j.arbres.2019.03.026. Epub 2019 May 24.
Ref 2 EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005 Feb 24;352(8):786-92. doi: 10.1056/NEJMoa044238.
Ref 3 Exosome-mediated transfer of lncRNA PART1 induces gefitinib resistance in esophageal squamous cell carcinoma via functioning as a competing endogenous RNA. J Exp Clin Cancer Res. 2018 Jul 27;37(1):171. doi: 10.1186/s13046-018-0845-9.
Ref 4 MiR-134/487b/655 cluster regulates TGF-Beta-induced epithelial-mesenchymal transition and drug resistance to gefitinib by targeting MAGI2 in lung adenocarcinoma cells. Mol Cancer Ther. 2014 Feb;13(2):444-53. doi: 10.1158/1535-7163.MCT-13-0448. Epub 2013 Nov 20.
Ref 5 MicroRNA-1 inhibits tumorigenicity of esophageal squamous cell carcinoma and enhances sensitivity to gefitinib. Oncol Lett. 2018 Jan;15(1):963-971. doi: 10.3892/ol.2017.7378. Epub 2017 Nov 9.
Ref 6 MicroRNA-147 induces a mesenchymal-to-epithelial transition (MET) and reverses EGFR inhibitor resistance. PLoS One. 2014 Jan 15;9(1):e84597. doi: 10.1371/journal.pone.0084597. eCollection 2014.
Ref 7 miR-27b synergizes with anticancer drugs via p53 activation and CYP1B1 suppression. Cell Res. 2015 Apr;25(4):477-95. doi: 10.1038/cr.2015.23. Epub 2015 Feb 20.
Ref 8 Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open. 2016 May 11;1(3):e000060. doi: 10.1136/esmoopen-2016-000060. eCollection 2016.
Ref 9 Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol. 2008 Jun 1;26(16):2745-53. doi: 10.1200/JCO.2007.15.6695.
Ref 10 Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol. 2010 Sep;5(9):1382-90. doi: 10.1097/JTO.0b013e3181eba657.
Ref 11 Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer. J Thorac Oncol. 2010 Oct;5(10):1623-9. doi: 10.1097/JTO.0b013e3181ec1531.
Ref 12 EGFR mutation conferring primary resistance to gefitinib in non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):207-8. doi: 10.1056/NEJM200507143530217.
Ref 13 Epidermal growth factor receptor mutations are associated with gefitinib sensitivity in non-small cell lung cancer in Japanese. Lung Cancer. 2006 Jan;51(1):71-7. doi: 10.1016/j.lungcan.2005.08.006. Epub 2005 Sep 29.
Ref 14 Mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitor in Korean patients with lung cancer. BMC Cancer. 2013 Dec 27;13:606. doi: 10.1186/1471-2407-13-606.
Ref 15 EGFR-Driven Behavior and Intrapatient T790M Mutation Heterogeneity of Non-Small-Cell Carcinoma With Squamous Histology. J Clin Oncol. 2015 Nov 1;33(31):e115-8. doi: 10.1200/JCO.2013.49.5697. Epub 2014 Apr 21.
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