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
• 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]
• 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 Validated by in-vivo Model for This Drug (1 diseases)
  Lung cancer [ICD-11: 2C25]; [4]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Esophageal cancer [ICD-11: 2B70]; [5]
  Lung cancer [ICD-11: 2C25]; [6]
• Target: Epidermal growth factor receptor (EGFR); EGFR_HUMAN; [1]
• 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

  MRAP: Metabolic Reprogramming via Altered Pathways

  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

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Epidermal growth factor receptor (EGFR) [7]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.41E-78; Fold-change: -3.81E-01; Z-score: -2.43E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133b suppresses the expression of EGFR, miR-133b transfection may modulate apoptosis, invasion and sensitivity to EGFR-TkI through the EGFR signaling pathways.

Key Molecule: Hepatocyte growth factor receptor (MET) [8]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.34E-10; Fold-change: -1.34E-01; Z-score: -6.52E+00
• 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
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: PC9GR cells; Lung; Homo sapiens (Human); CVCL_V337
• Experiment for Molecule Alteration: Western blot 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: Hepatocyte growth factor receptor (MET) [9]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.34E-10; Fold-change: -1.34E-01; Z-score: -6.52E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: HGF/ MET signaling pathway; Inhibition; hsa04151
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: 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: Epidermal growth factor receptor (EGFR) [10]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.41E-78; Fold-change: -3.81E-01; Z-score: -2.43E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: 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) [11]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.41E-78; Fold-change: -3.81E-01; Z-score: -2.43E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: CCD-19Lu cells; Lung; Homo sapiens (Human); CVCL_2382
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: 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: Hepatocyte growth factor receptor (MET) [11]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.34E-10; Fold-change: -1.34E-01; Z-score: -6.52E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: CCD-19Lu cells; Lung; Homo sapiens (Human); CVCL_2382
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: 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: Caspase-1 (CASP1) [12]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.59E-08; Fold-change: 2.75E-01; Z-score: 5.64E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR377/CASP1 signaling pathway; Regulation; N.A.
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• 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: 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) [13]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.34E-10; Fold-change: -1.34E-01; Z-score: -6.52E+00
• 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: Ubiquitin carboxyl-terminal hydrolase 14 (USP14) [17]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.26E-02; Fold-change: -5.27E-02; Z-score: -1.87E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: 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: Transcriptional coactivator YAP1 (YAP1) [20]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.98E-07; Fold-change: -1.85E-01; Z-score: -5.39E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: 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) [21]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.76E-01; Fold-change: -2.32E-02; Z-score: -8.88E-01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: 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: Zinc finger E-box-binding homeobox 1 (ZEB1) [22]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.74E-02; Fold-change: -1.61E-01; Z-score: -2.40E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 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: Tripartite motif-containing protein 16 (TRIM16) [23]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.34E-02; Fold-change: -1.04E-01; Z-score: -2.04E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: JAKT/STAT signaling pathway; Inhibition; hsa04630
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: H4006 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: 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: Epidermal growth factor receptor (EGFR) [31]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.65E-01; Fold-change: 1.45E-02; Z-score: 1.39E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: 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: Adhesion G protein-coupled receptor A2 (ADGRA2) [33]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.93E-20; Fold-change: -7.36E-02; Z-score: -9.79E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Western blot 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.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Protein Wnt-5a (WNT5A) [28]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.08E-09; Fold-change: 6.39E-02; Z-score: 6.09E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: 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: Zinc finger E-box-binding homeobox 1 (ZEB1) [37]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.29E-79; Fold-change: -2.78E-01; Z-score: -2.61E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MEK/ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; N.A.
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 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.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Growth arrest specific 5 (GAS5) [10]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Lung
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.78E-12; Fold-change: 6.09E-01; Z-score: 7.06E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: 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: Small nucleolar RNA host gene 5 (SNHG5) [12]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Lung
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.53E-04; Fold-change: 2.31E-01; Z-score: 3.42E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR377/CASP1 signaling pathway; Regulation; N.A.
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• 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: 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-135a [23]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: JAKT/STAT signaling pathway; Inhibition; hsa04630
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: H4006 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: 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 [67]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: HCC827/GR cells; Lung; Homo sapiens (Human); CVCL_V620
• In Vitro Model: 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 [22]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 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 [21]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: 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 [68]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• 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
• In Vitro Model: 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 [13]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Up-regulation
• 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 [20]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: 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) [69]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: 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 [17]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: 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: hsa-mir-377 [12]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR377/CASP1 signaling pathway; Regulation; N.A.
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• 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: 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 [11]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: CCD-19Lu cells; Lung; Homo sapiens (Human); CVCL_2382
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: 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: hsa-mir-7 [31]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: 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 [9]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: HGF/ MET signaling pathway; Inhibition; hsa04151
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: 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 [8]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• 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
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: 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 [33]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• 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 [39]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: 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 [70]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210
• Cell Pathway Regulation: 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 [7]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: 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.

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [32]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Missense mutation; p.L858R
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.64 Å; PDB: 4LI5
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.47 Å; PDB: 2ITV

RMSD: 1.34; TM score: 0.90001; Amino acid change: L858R

• 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) [32]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Frameshift mutation; p.E746-A750del
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK/MAPKsignaling pathway; Activation; hsa04210
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy; ATP-binding pocket affinity comparison assay
• Mechanism Description: The two most common EGFR-activating mutations are small in-frame deletions in exon 19 (particularly E746-A750del) and amino acid substitution in exon 21 (leucine to arginine at codon 858 (L858R)), which collectively account for >90% of known activating EGFR mutations.2 3 These two alterations are the best-characterised mutations conferring sensitivity to EGFR-tyrosine kinase inhibitor (EGFR-TkI) therapy, resulting in higher response rates (RR) (up to 70%) and longer median survival (up to 24-30 months) than those observed in patients with wild-type (WT) EGFR. The higher sensitivity of these mutations relays in an increased affinity of the ATP-binding pocket for EGFR-TkIs as compared with WT EGFR.

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Hepatocyte growth factor receptor (MET) [14]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.34E-10; Fold-change: -1.34E-01; Z-score: -6.52E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: miR19a/c-Met signaling pathway; Regulation; N.A.
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 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: Gem-associated protein 2 (SIP1) [27]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.13E-19; Fold-change: 9.33E-02; Z-score: 9.40E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta-catenin signaling pathway; Activation; hsa04520
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 95D cells; Lung; Homo sapiens (Human); CVCL_7110
• In Vitro Model: 95C cells; Lung; Homo sapiens (Human); CVCL_7109
• In Vitro Model: 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: Membrane-associated guanylate kinase inverted 2 (MAGI2) [6]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.14E-03; Fold-change: -3.11E-02; Z-score: -2.66E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC-14 cells; Lung; Homo sapiens (Human); CVCL_1640
• In Vitro Model: LC-2/ad cells; Lung; Homo sapiens (Human); CVCL_1373
• In Vitro Model: RERF-LCkJ cells; Lung; Homo sapiens (Human); CVCL_1654
• In Vitro Model: ABC-1 cells; Lung; Homo sapiens (Human); CVCL_1066
• In Vitro Model: 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-19a [14]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• Cell Pathway Regulation: miR19a/c-Met signaling pathway; Regulation; N.A.
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 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: HOX transcript antisense RNA (HOTAIR) [27]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta-catenin signaling pathway; Activation; hsa04520
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• In Vitro Model: 95D cells; Lung; Homo sapiens (Human); CVCL_7110
• In Vitro Model: 95C cells; Lung; Homo sapiens (Human); CVCL_7109
• In Vitro Model: 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: hsa-mir-134 [6]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC-14 cells; Lung; Homo sapiens (Human); CVCL_1640
• In Vitro Model: LC-2/ad cells; Lung; Homo sapiens (Human); CVCL_1373
• In Vitro Model: RERF-LCkJ cells; Lung; Homo sapiens (Human); CVCL_1654
• In Vitro Model: ABC-1 cells; Lung; Homo sapiens (Human); CVCL_1066
• In Vitro Model: 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 [6]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC-14 cells; Lung; Homo sapiens (Human); CVCL_1640
• In Vitro Model: LC-2/ad cells; Lung; Homo sapiens (Human); CVCL_1373
• In Vitro Model: RERF-LCkJ cells; Lung; Homo sapiens (Human); CVCL_1654
• In Vitro Model: ABC-1 cells; Lung; Homo sapiens (Human); CVCL_1066
• In Vitro Model: 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.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) [15]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung carcinoma
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.38E-05; Fold-change: 6.29E-01; Z-score: 4.51E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice , with PC-9/GR cell lines; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B3 axis in NSCLC.

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) [15]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung carcinoma
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.38E-05; Fold-change: 6.29E-01; Z-score: 4.51E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice , with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B2 axis in NSCLC.

Key Molecule: Epidermal growth factor receptor (EGFR) [59]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Activation; hsa04390
• In Vivo Model: Female BALB/c-nu mice, with PC9 and PC9GR cells; Mice
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC11 cells, and the YAP expression was inhibited by pitavastatin administration.

Key Molecule: Epidermal growth factor receptor (EGFR) [59]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Activation; hsa04390
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration.

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [60]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT1 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [60]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC-9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT2 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [60]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT3 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [60]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_B0JT
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT4 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [60]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Male nude mice; Mice
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT5 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Key Molecule: Cytochrome c oxidase subunit 6B2 (COX6B2) [15]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice , with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B2 axis in NSCLC.

Key Molecule: Cytochrome c oxidase subunit 6B2 (COX6B2) [15]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice , with PC-9/GR cell lines; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B3 axis in NSCLC.

Key Molecule: . [61]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Fibroblast cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Gefitinib-resistant NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: H1975 parental cells; Lung; Homo sapiens (Human); CVCL_1511
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells.

Key Molecule: . [61]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vivo Model: NCI-H1975 xenograft-bearing mice; nude mice bearing AR cell subcutaneous xenografts; Mice
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Programmed cell death protein 4 (PDCD4) [16]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.36E-04; Fold-change: -1.45E-01; Z-score: -3.53E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9R cells; Lung; Homo sapiens (Human); CVCL_D778
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot 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: Epidermal growth factor receptor (EGFR) [18]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.37E-11; Fold-change: 6.31E-01; Z-score: 7.28E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: 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: Apoptotic protease-activating factor 1 (APAF1) [19]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.29E-05; Fold-change: -1.11E-01; Z-score: -4.51E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: 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) [24]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.37E-11; Fold-change: 6.31E-01; Z-score: 7.28E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: 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: Catenin delta-1 (CTNND1) [25]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.34E-02; Fold-change: -5.18E-02; Z-score: -1.80E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: 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: TGF-beta receptor type II (TGFBR2) [26]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.29E-63; Fold-change: -9.29E-01; Z-score: -2.52E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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: Phosphatase and tensin homolog (PTEN) [32]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.01E-01; Fold-change: -9.25E-03; Z-score: -1.64E+00
• 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: Tyrosine-protein phosphatase non-receptor type 13 (PTPN13) [34]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.34E-09; Fold-change: -8.21E-02; Z-score: -6.22E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR signaling pathway; Activation; hsa01521
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: H2170 cells; Lung; Homo sapiens (Human); CVCL_1535
• In Vitro Model: 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: Growth arrest-specific protein 7 (GAS7) [35]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.21E-48; Fold-change: -1.41E-01; Z-score: -1.69E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Regulation; N.A.
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 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: Caspase-1 (CASP1) [12]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.09E-84; Fold-change: -1.65E-01; Z-score: -2.30E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR377/CASP1 signaling pathway; Regulation; N.A.
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• 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: 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: Cellular tumor antigen p53 (TP53) [62]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Missense mutation; p.Y163C
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.05 Å; PDB: 2OCJ
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.65 Å; PDB: 8QWL

RMSD: 0.52; TM score: 0.99068; Amino acid change: Y163C

• 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: Epidermal growth factor receptor (EGFR) [62]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Missense mutation; p.T790M
• Wild Type Structure: Method: X-ray diffraction; Resolution: 3.10 Å; PDB: 2J6M
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.05 Å; PDB: 2JIU

RMSD: 1.57; TM score: 0.92063; Amino acid change: T790M

• 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: phosphoinositide-3-dependent protein kinase 1 (PDPK1) [52]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: miR1183/PDPk1 signaling pathway; Activation; hsa05206
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: 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: RAC serine/threonine-protein kinase (AKT) [30]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: 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) [54]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: 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: Zinc finger protein GLI1 (GLI1) [55]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: 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: Transcriptional coactivator YAP1 (YAP1) [56]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR630/YAP1/ERK signaling pathway; Regulation; N.A.
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9GR cells; Lung; Homo sapiens (Human); CVCL_V337
• In Vitro Model: 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) [57]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: 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: Phosphatase and tensin homolog (PTEN) [58]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: 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: Phosphatase and tensin homolog (PTEN) [16]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9R cells; Lung; Homo sapiens (Human); CVCL_D778
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot 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) [32]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Structural variation; Copy number loss
• 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) [32]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Mutation; .
• 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: DNA-binding factor KBF1 (p105) (NFKB1) [62]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Missense mutation; p.G489V
• 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: Hepatocyte growth factor receptor (MET) [48]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Molecule Alteration: Structural variation; Amplification
• 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) [48]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Molecule Alteration: Mutation; .
• 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) [49]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Mutation; .
• 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) [49]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Molecule Alteration: Structural variation; Copy number gain
• 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) [49]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Molecule Alteration: Mutation; .
• 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) [49]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Molecule Alteration: Structural variation; Copy number gain
• 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) [49]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Molecule Alteration: Mutation; .
• 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) [62]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Missense mutation; p.G489V
• 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) [50]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next generation sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall or disease-free survival assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutantalleles in association with emergence of therapy resistance. These included an activating mutation in PIk3CA.

Key Molecule: Hepatocyte growth factor receptor (MET) [63]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Activation
• Cell Pathway Regulation: HGF-Met signaling pathway; Regulation; N.A.
• Mechanism Description: Aberrant Met amplification and HGF-Met signaling pathway activation have been proven to be the main mechanism of acquired resistance of EGFR inhibition by small molecules, such as erlotinib and gefitinib.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [64]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: PC9/GR cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Apoptosis assay
• Mechanism Description: Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of beta-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, beta-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [64]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Loss
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: HCC827/GR cells; N.A.; Homo sapiens (Human); CVCL_E7R9
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Apoptosis assay
• Mechanism Description: Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of beta-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, beta-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib.

Key Molecule: Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB) [65]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Ca2+/calcineurin/MEK/ERK1/2 signaling pathway; Regulation; N.A.
• In Vitro Model: PC9/DR cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: PC9/GR cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: PC9/OR cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTS assay; Flow cytometric assay; Colony formation assay
• Mechanism Description: Here, we show that a?PPP3CB?transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of?PPP3CB?by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment.

Key Molecule: Programmed cell death 1 ligand 1 (PD-L1) [66]

• Resistant Disease: egfr-mutant luad [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: PC-9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our results suggested that PD-L1 might play a role in promoting autophagy and inhibiting apoptosis, which was responsible for the generation of primary resistance to EGFR-TKIs, and the combination therapy exerted a synergistic antitumor effect by inhibiting the activation of the MAPK/ERK signaling pathway.

Key Molecule: Programmed cell death 1 ligand 1 (PD-L1) [66]

• Resistant Disease: egfr-mutant luad [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our results suggested that PD-L1 might play a role in promoting autophagy and inhibiting apoptosis, which was responsible for the generation of primary resistance to EGFR-TKIs, and the combination therapy exerted a synergistic antitumor effect by inhibiting the activation of the MAPK/ERK signaling pathway.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA 460 (LINC00460) [24]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Lung
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.91E-10; Fold-change: 4.46E+00; Z-score: 6.44E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: 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: MIR31 host gene (MIR31HG) [29]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Lung
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.75E-14; Fold-change: 2.93E+00; Z-score: 7.81E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/PI3K/AKT signaling pathway; Regulation; N.A.
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 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) [30]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung adenocarcinoma
• The Studied Tissue: Lung
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.27E-47; Fold-change: 1.83E+00; Z-score: 1.60E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: 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-200a [1]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Down-regulation
• 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]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Up-regulation
• 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) [26]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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 [26]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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) [25]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: 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 [25]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: 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 [24]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: 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 [52]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: miR1183/PDPk1 signaling pathway; Activation; hsa05206
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: 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 [52]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: miR1183/PDPk1 signaling pathway; Activation; hsa05206
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: 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 [35]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Regulation; N.A.
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 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 [53]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: 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 [53]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: 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 [53]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: 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-214 [54]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: 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 [19]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: 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 [18]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: 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 [55]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: 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) [12]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR377/CASP1 signaling pathway; Regulation; N.A.
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• 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: 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 [56]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR630/YAP1/ERK signaling pathway; Regulation; N.A.
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9GR cells; Lung; Homo sapiens (Human); CVCL_V337
• In Vitro Model: 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 [57]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: 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 [34]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR signaling pathway; Activation; hsa01521
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: H2170 cells; Lung; Homo sapiens (Human); CVCL_1535
• In Vitro Model: 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 [58]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: 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 [16]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 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.

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [32]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Missense mutation; p.C797S
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.64 Å; PDB: 4LI5
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.20 Å; PDB: 6JRX

RMSD: 1.53; TM score: 0.92164; Amino acid change: C797S

• 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) [40], [41], [42]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Missense mutation; p.T790M
• Wild Type Structure: Method: X-ray diffraction; Resolution: 3.10 Å; PDB: 2J6M
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.05 Å; PDB: 2JIU

RMSD: 1.57; TM score: 0.92063; Amino acid change: T790M

• 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], [43], [44]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.T790M
• Wild Type Structure: Method: X-ray diffraction; Resolution: 3.10 Å; PDB: 2J6M
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.05 Å; PDB: 2JIU

RMSD: 1.57; TM score: 0.92063; Amino acid change: T790M

• 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) [45], [46], [47]

• Resistant Disease: Lung squamous cell carcinoma [ICD-11: 2C25.3]
• Molecule Alteration: Missense mutation; p.T790M
• Wild Type Structure: Method: X-ray diffraction; Resolution: 3.10 Å; PDB: 2J6M
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.05 Å; PDB: 2JIU

RMSD: 1.57; TM score: 0.92063; Amino acid change: T790M

• 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) [48]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Molecule Alteration: Missense mutation; p.T790M
• Wild Type Structure: Method: X-ray diffraction; Resolution: 3.10 Å; PDB: 2J6M
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.05 Å; PDB: 2JIU

RMSD: 1.57; TM score: 0.92063; Amino acid change: T790M

• 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) [49]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Molecule Alteration: Missense mutation; p.T790M
• Wild Type Structure: Method: X-ray diffraction; Resolution: 3.10 Å; PDB: 2J6M
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.05 Å; PDB: 2JIU

RMSD: 1.57; TM score: 0.92063; Amino acid change: T790M

• 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) [50]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Missense mutation; p.T790M
• Wild Type Structure: Method: X-ray diffraction; Resolution: 3.10 Å; PDB: 2J6M
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.05 Å; PDB: 2JIU

RMSD: 1.57; TM score: 0.92063; Amino acid change: T790M

• 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]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Missense mutation; p.T790M
• Wild Type Structure: Method: X-ray diffraction; Resolution: 3.10 Å; PDB: 2J6M
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.05 Å; PDB: 2JIU

RMSD: 1.57; TM score: 0.92063; Amino acid change: T790M

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cos-7 cells; Lung; Homo sapiens (Human); CVCL_0224
• In Vitro Model: 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]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Missense mutation; p.T790M
• Wild Type Structure: Method: X-ray diffraction; Resolution: 3.10 Å; PDB: 2J6M
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.05 Å; PDB: 2JIU

RMSD: 1.57; TM score: 0.92063; Amino acid change: T790M

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cos-7 cells; Lung; Homo sapiens (Human); CVCL_0224
• In Vitro Model: 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) [32]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Missense mutation; p.C797S+p.T790M
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.64 Å; PDB: 4LI5
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.20 Å; PDB: 6JRX

RMSD: 1.53; TM score: 0.92164; Amino acid change: C797S+T790M

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/TKLS mediated apoptosis signaling pathway; Inhibition; hsa01521
• Cell Pathway Regulation: 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) [51]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.D761Y
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct Sanger sequencing analysis
• Experiment for Drug Resistance: CellTiter-Blue cell viability assay
• Mechanism Description: The T790M mutation is common in patients with acquired resistance. The limited spectrum of TkI-resistant mutations in EGFR, which binds to erlotinib in the active conformation, contrasts with a wider range of second-site mutations seen with acquired resistance to imatinib, which binds to ABL and kIT, respectively, in closed conformations. Collectively, our data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomic site and mode of binding to the kinase target.

Key Molecule: Epidermal growth factor receptor (EGFR) [49]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Molecule Alteration: Missense mutation; p.L747S
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure.

Key Molecule: Epidermal growth factor receptor (EGFR) [49]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Molecule Alteration: Missense mutation; p.D761Y
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure.

Key Molecule: Thymidylate synthase (TYMS) [4]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Patient-derived advanced NSCLC model; Homo sapiens
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: In our study, we first illustrated the role of TS-mediated thymidylate nucleotide biosynthesis in the development of gefitinib resistance. We demonstrated that NSCLC patients with higher expression of TS gene have shorter PFS during EGFR-TKI treatment. Furthermore, we found TS is upregulated in NSCLC patients resistant to gefitinib and in PC9/GR cells which are tolerant of gefitinib. Knockdown of TS-induced apoptosis and diminished survival of gefitinib-resistant NSCLC.

Key Molecule: Thymidylate synthase (TYMS) [4]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC827/GR cells; N.A.; Homo sapiens (Human); CVCL_E7R9
• In Vitro Model: PC9/GR cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: In our study, we first illustrated the role of TS-mediated thymidylate nucleotide biosynthesis in the development of gefitinib resistance. We demonstrated that NSCLC patients with higher expression of TS gene have shorter PFS during EGFR-TKI treatment. Furthermore, we found TS is upregulated in NSCLC patients resistant to gefitinib and in PC9/GR cells which are tolerant of gefitinib. Knockdown of TS-induced apoptosis and diminished survival of gefitinib-resistant NSCLC.

Key Molecule: Epidermal growth factor receptor (EGFR) [3]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Mutation; .
• Experiment for Drug Resistance: Statistical analysis
• Mechanism Description: EGFR-TKI Rechallenge With Another TKI may be a useful treatment option after first-line osimertinib.

Kidney cancer [ICD-11: 2C90]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [36]

• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Renal cancer
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.73E-03; Fold-change: -1.49E-01; Z-score: -3.05E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; N.A.
• In Vitro Model: 769-P cells; Kidney; Homo sapiens (Human); CVCL_1050
• In Vitro Model: 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.

Esophageal cancer [ICD-11: 2B70]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [5]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR129/BCL2 signaling pathway; Regulation; N.A.
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: KYSE-450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• In Vitro Model: TE6 cells; Esophageal; Homo sapiens (Human); CVCL_1765
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: 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) [5]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR129/BCL2 signaling pathway; Regulation; N.A.
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: KYSE-450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• In Vitro Model: TE6 cells; Esophageal; Homo sapiens (Human); CVCL_1765
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: 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 [5]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR129/BCL2 signaling pathway; Regulation; N.A.
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: KYSE-450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• In Vitro Model: TE6 cells; Esophageal; Homo sapiens (Human); CVCL_1765
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: 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) [5]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR129/BCL2 signaling pathway; Regulation; N.A.
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: KYSE-450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• In Vitro Model: TE6 cells; Esophageal; Homo sapiens (Human); CVCL_1765
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: 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)

Key Molecule: hsa-mir-1 [38]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: 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)

Key Molecule: PI3-kinase alpha (PIK3CA) [38]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: 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]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-147 [39]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: 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]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [36]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; N.A.
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: 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)

Key Molecule: hsa-mir-27b [36]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; N.A.
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: 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)

Key Molecule: Cyclin-G1 (CCNG1) [36]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; N.A.
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: 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.

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: Real-World Study of EGFR-TKI Rechallenge With Another TKI After First-Line Osimertinib Discontinuation in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: A Subset Analysis of the Reiwa Study. Thorac Cancer. 2025 Jan;16(2):e15507.
• Ref 4: Pemetrexed induces ROS generation and cellular senescence by attenuating TS-mediated thymidylate metabolism to reverse gefitinib resistance in NSCLC. J Cell Mol Med. 2023 Jul;27(14):2032-2044.
• Ref 5: 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 6: 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 7: MicroRNA-133b inhibits the growth of non-small-cell lung cancer by targeting the epidermal growth factor receptor. FEBS J. 2012 Oct;279(20):3800-12. doi: 10.1111/j.1742-4658.2012.08741.x. Epub 2012 Sep 11.
• Ref 8: MiR-130a overcomes gefitinib resistance by targeting met in non-small cell lung cancer cell lines. Asian Pac J Cancer Prev. 2014;15(3):1391-6. doi: 10.7314/apjcp.2014.15.3.1391.
• Ref 9: MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET. Cancer Lett. 2014 Sep 1;351(2):265-71. doi: 10.1016/j.canlet.2014.06.010. Epub 2014 Jun 28.
• Ref 10: The long non-coding RNA, GAS5, enhances gefitinib-induced cell death in innate EGFR tyrosine kinase inhibitor-resistant lung adenocarcinoma cells with wide-type EGFR via downregulation of the IGF-1R expression. J Hematol Oncol. 2015 Apr 29;8:43. doi: 10.1186/s13045-015-0140-6.
• Ref 11: MicroRNA-200a Targets EGFR and c-Met to Inhibit Migration, Invasion, and Gefitinib Resistance in Non-Small Cell Lung Cancer. Cytogenet Genome Res. 2015;146(1):1-8. doi: 10.1159/000434741. Epub 2015 Jul 11.
• Ref 12: The long non-coding RNA SNHG5 regulates gefitinib resistance in lung adenocarcinoma cells by targetting miR-377/CASP1 axis. Biosci Rep. 2018 Aug 29;38(4):BSR20180400. doi: 10.1042/BSR20180400. Print 2018 Aug 31.
• Ref 13: MiR-128 reverses the gefitinib resistance of the lung cancer stem cells by inhibiting the c-met/PI3K/AKT pathway. Oncotarget. 2016 Nov 8;7(45):73188-73199. doi: 10.18632/oncotarget.12283.
• Ref 14: miR-19a contributes to gefitinib resistance and epithelial mesenchymal transition in non-small cell lung cancer cells by targeting c-Met. Sci Rep. 2017 Jun 7;7(1):2939. doi: 10.1038/s41598-017-01153-0.
• Ref 15: Metabolic Reprogramming Driven by IGF2BP3 Promotes Acquired Resistance to EGFR Inhibitors in Non-Small Cell Lung Cancer. Cancer Res. 2023 Jul 5;83(13):2187-2207.
• Ref 16: MiR-21 overexpression is associated with acquired resistance of EGFR-TKI in non-small cell lung cancer. Lung Cancer. 2014 Feb;83(2):146-53. doi: 10.1016/j.lungcan.2013.11.003. Epub 2013 Nov 13.
• Ref 17: Tumor suppressive microRNA-124a inhibits stemness and enhances gefitinib sensitivity of non-small cell lung cancer cells by targeting ubiquitin-specific protease 14. Cancer Lett. 2018 Jul 28;427:74-84. doi: 10.1016/j.canlet.2018.04.022. Epub 2018 Apr 24.
• Ref 18: HOXA4-regulated miR-138 suppresses proliferation and gefitinib resistance in non-small cell lung cancer. Mol Genet Genomics. 2019 Feb;294(1):85-93. doi: 10.1007/s00438-018-1489-3. Epub 2018 Sep 8.
• Ref 19: [Mechanism of miR-221 contributes to gefitinib resistance in PC-9 cells]. Zhonghua Yi Xue Za Zhi. 2018 Nov 13;98(42):3447-3452. doi: 10.3760/cma.j.issn.0376-2491.2018.42.014.
• Ref 20: MicroRNA 506 3p reverses gefitinib resistance in non small cell lung cancer by targeting Yes associated protein 1. Mol Med Rep. 2019 Feb;19(2):1331-1339. doi: 10.3892/mmr.2018.9710. Epub 2018 Nov 29.
• Ref 21: miR-124 modulates gefitinib resistance through SNAI2 and STAT3 in non-small cell lung cancer. J Huazhong Univ Sci Technolog Med Sci. 2016 Dec;36(6):839-845. doi: 10.1007/s11596-016-1672-x. Epub 2016 Dec 7.
• Ref 22: miR-200c 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. Biomed Pharmacother. 2017 Jan;85:113-119. doi: 10.1016/j.biopha.2016.11.100. Epub 2016 Dec 5.
• Ref 23: Downregulation of MicroRNA-135 Promotes Sensitivity of Non-Small Cell Lung Cancer to Gefitinib by Targeting TRIM16. Oncol Res. 2018 Aug 23;26(7):1005-1014. doi: 10.3727/096504017X15144755633680. Epub 2018 Jan 2.
• Ref 24: Long Noncoding RNA LINC00460 Promotes the Gefitinib Resistance of Nonsmall Cell Lung Cancer Through Epidermal Growth Factor Receptor by Sponging miR-769-5p. DNA Cell Biol. 2019 Feb;38(2):176-183. doi: 10.1089/dna.2018.4462. Epub 2019 Jan 2.
• Ref 25: LncRNA MALAT1 Depressed Chemo-Sensitivity of NSCLC Cells through Directly Functioning on miR-197-3p/p120 Catenin Axis. Mol Cells. 2019 Mar 31;42(3):270-283. doi: 10.14348/molcells.2019.2364. Epub 2019 Feb 19.
• Ref 26: microRNA-301b-3p downregulation underlies a novel inhibitory role of long non-coding RNA MBNL1-AS1 in non-small cell lung cancer. Stem Cell Res Ther. 2019 May 21;10(1):144. doi: 10.1186/s13287-019-1235-8.
• Ref 27: HOTAIR, a long noncoding RNA, is a marker of abnormal cell cycle regulation in lung cancer. Cancer Sci. 2018 Sep;109(9):2717-2733. doi: 10.1111/cas.13745.
• Ref 28: Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer. Cell Death Dis. 2014 May 15;5(5):e1227. doi: 10.1038/cddis.2014.186.
• Ref 29: Increased MIR31HG lncRNA expression increases gefitinib resistance in non-small cell lung cancer cell lines through the EGFR/PI3K/AKT signaling pathway. Oncol Lett. 2017 May;13(5):3494-3500. doi: 10.3892/ol.2017.5878. Epub 2017 Mar 20.
• Ref 30: LINC00665 Induces Acquired Resistance to Gefitinib through Recruiting EZH2 and Activating PI3K/AKT Pathway in NSCLC. Mol Ther Nucleic Acids. 2019 Jun 7;16:155-161. doi: 10.1016/j.omtn.2019.02.010. Epub 2019 Feb 21.
• Ref 31: MicroRNA expression profiles associated with acquired gefitinib-resistance in human lung adenocarcinoma cells. Mol Med Rep. 2015 Jan;11(1):333-40. doi: 10.3892/mmr.2014.2757. Epub 2014 Oct 23.
• Ref 32: 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 33: miR-138-5p reverses gefitinib resistance in non-small cell lung cancer cells via negatively regulating G protein-coupled receptor 124. Biochem Biophys Res Commun. 2014 Mar 28;446(1):179-86. doi: 10.1016/j.bbrc.2014.02.073. Epub 2014 Feb 28.
• Ref 34: miR-26a desensitizes non-small cell lung cancer cells to tyrosine kinase inhibitors by targeting PTPN13. Oncotarget. 2016 Jul 19;7(29):45687-45701. doi: 10.18632/oncotarget.9920.
• Ref 35: MiR-181a contributes gefitinib resistance in non-small cell lung cancer cells by targeting GAS7. Biochem Biophys Res Commun. 2018 Jan 22;495(4):2482-2489. doi: 10.1016/j.bbrc.2017.12.096. Epub 2017 Dec 18.
• Ref 36: 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 37: miR-200c overexpression is associated with better efficacy of EGFR-TKIs in non-small cell lung cancer patients with EGFR wild-type. Oncotarget. 2014 Sep 15;5(17):7902-16. doi: 10.18632/oncotarget.2302.
• Ref 38: 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 39: 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 40: 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 41: 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 42: 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 43: 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 44: 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 45: 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 46: 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.
• Ref 47: Squamous Cell Carcinoma "Transformation" Concurrent with Secondary T790M Mutation in Resistant EGFR-Mutated Adenocarcinomas. J Thorac Oncol. 2016 Apr;11(4):e49-51. doi: 10.1016/j.jtho.2015.12.096. Epub 2015 Dec 30.
• Ref 48: Noninvasive monitoring of the genetic evolution of EGFR-mutant non-small-cell lung cancer by analyzing circulating tumor DNA during combination chemotherapy with gefitinib and pemetrexed or S-1. Onco Targets Ther. 2016 Aug 24;9:5287-95. doi: 10.2147/OTT.S105976. eCollection 2016.
• Ref 49: Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014 Aug;11(8):473-81. doi: 10.1038/nrclinonc.2014.104. Epub 2014 Jul 1.
• Ref 50: Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013 Aug;10(8):472-84. doi: 10.1038/nrclinonc.2013.110. Epub 2013 Jul 9.
• Ref 51: Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res. 2006 Nov 1;12(21):6494-501. doi: 10.1158/1078-0432.CCR-06-1570.
• Ref 52: Circular RNA hsa_circ_0004015 regulates the proliferation, invasion, and TKI drug resistance of non-small cell lung cancer by miR-1183/PDPK1 signaling pathway. Biochem Biophys Res Commun. 2019 Jan 8;508(2):527-535. doi: 10.1016/j.bbrc.2018.11.157. Epub 2018 Nov 30.
• Ref 53: The relationship between miR-17-5p, miR-92a, and let-7b expression with non-small cell lung cancer targeted drug resistance. J BUON. 2017 Mar-Apr;22(2):454-461.
• Ref 54: Exosomal transfer of miR-214 mediates gefitinib resistance in non-small cell lung cancer. Biochem Biophys Res Commun. 2018 Dec 9;507(1-4):457-464. doi: 10.1016/j.bbrc.2018.11.061. Epub 2018 Nov 17.
• Ref 55: MiR-873 inhibition enhances gefitinib resistance in non-small cell lung cancer cells by targeting glioma-associated oncogene homolog 1. Thorac Cancer. 2018 Oct;9(10):1262-1270. doi: 10.1111/1759-7714.12830. Epub 2018 Aug 20.
• Ref 56: A low microRNA-630 expression confers resistance to tyrosine kinase inhibitors in EGFR-mutated lung adenocarcinomas via miR-630/YAP1/ERK feedback loop. Theranostics. 2018 Feb 2;8(5):1256-1269. doi: 10.7150/thno.22048. eCollection 2018.
• Ref 57: miR-135a Confers Resistance to Gefitinib in Non-Small Cell Lung Cancer Cells by Upregulation of RAC1. Oncol Res. 2018 Sep 14;26(8):1191-1200. doi: 10.3727/096504018X15166204902353. Epub 2018 Jan 31.
• Ref 58: Alteration in Mir-21/PTEN expression modulates gefitinib resistance in non-small cell lung cancer. PLoS One. 2014 Jul 24;9(7):e103305. doi: 10.1371/journal.pone.0103305. eCollection 2014.
• Ref 59: Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway. Cancer Cell Int. 2024 Jun 28;24(1):224.
• Ref 60: HIF-1alpha-HPRT1 axis promotes tumorigenesis and gefitinib resistance by enhancing purine metabolism in EGFR-mutant lung adenocarcinoma. J Exp Clin Cancer Res. 2024 Sep 30;43(1):269.
• Ref 61: Epigallocatechin gallate circumvents drug-induced resistance in non-small-cell lung cancer by modulating glucose metabolism and AMPK/AKT/MAPK axis. Phytother Res. 2023 Dec;37(12):5837-5853.
• Ref 62: Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013 May 2;497(7447):108-12. doi: 10.1038/nature12065. Epub 2013 Apr 7.
• Ref 63: Targeting BET proteins inhibited the growth of non-small cell lung carcinoma through downregulation of Met expression. Cell Biol Int. 2023 Mar;47(3):622-633.
• Ref 64: beta-Elemene Reverses Gefitinib Resistance in NSCLC Cells by Inhibiting lncRNA H19-Mediated Autophagy. Pharmaceuticals (Basel). 2024 May 14;17(5):626.
• Ref 65: PPP3CB overexpression mediates EGFR TKI resistance in lung tumors via calcineurin/MEK/ERK signaling. Life Sci Alliance. 2024 Oct 1;7(12):e202402873.
• Ref 66: PD-L1 induces autophagy and primary resistance to EGFR-TKIs in EGFR-mutant lung adenocarcinoma via the MAPK signaling pathway. Cell Death Dis. 2024 Aug 1;15(8):555.
• Ref 67: MicroRNA-30e reduces cell growth and enhances drug sensitivity to gefitinib in lung carcinoma. Oncotarget. 2017 Jan 17;8(3):4572-4581. doi: 10.18632/oncotarget.13944.
• Ref 68: MiR-30a-5p Overexpression May Overcome EGFR-Inhibitor Resistance through Regulating PI3K/AKT Signaling Pathway in Non-small Cell Lung Cancer Cell Lines. Front Genet. 2016 Nov 15;7:197. doi: 10.3389/fgene.2016.00197. eCollection 2016.
• Ref 69: Polyphyllin I modulates MALAT1/STAT3 signaling to induce apoptosis in gefitinib-resistant non-small cell lung cancer. Toxicol Appl Pharmacol. 2018 Oct 1;356:1-7. doi: 10.1016/j.taap.2018.07.031. Epub 2018 Aug 1.
• Ref 70: Fulvestrant increases gefitinib sensitivity in non-small cell lung cancer cells by upregulating let-7c expression. Biomed Pharmacother. 2014 Apr;68(3):307-13. doi: 10.1016/j.biopha.2013.10.007. Epub 2013 Nov 7.