Drug Information

Drug (ID: DG00101) and It's Reported Resistant Information

• Name: Erlotinib
• Synonyms: Erlotinin; Tarceva; Erlotinib Base; OSI 744; R 1415; CP 358,774; CP-358774; Erlotinib(Tarceva); Tarceva (TN); CP-358,774; Erlotinib, OS-774; N-(3-ethynylphenyl)[6,7-bis(2-methoxyethoxy)quinazolin-4-yl]amine; N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine; N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine; N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-Quinazolinamine; [6,7-BIS(2-METHOXY-ETHOXY)QUINAZOLINE-4-YL]-(3-ETHYNYLPHENYL)AMINE; [6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine; 4-[(3-Ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline; 4-[(3-ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline
• Indication:
  In total 3 Indication(s)
  Lung cancer [ICD-11: 2C25]; Approved; [1]
  Pancreatic cancer [ICD-11: 2C10]; Phase 3; [1]
  Colon cancer [ICD-11: 2B90]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Lactic acidosis [ICD-11: 5C73]; [2]
  Lung cancer [ICD-11: 2C25]; [3], [4], [5]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Lung cancer [ICD-11: 2C25]; [6]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [7]
• Target: Epidermal growth factor receptor (EGFR); EGFR_HUMAN; [1]
• Formula: C22H23N3O4
• IsoSMILES: COCCOC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=CC(=C3)C#C)OCCOC
• InChI: 1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
• InChIKey: AAKJLRGGTJKAMG-UHFFFAOYSA-N
• PubChem CID: 176870
• ChEBI ID: CHEBI:114785
• TTD Drug ID: D07POC
• VARIDT ID: DR00558
• DrugBank ID: DB00530

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [7]

• Molecule Alteration: Duplication; p.Y772_A775 (c.2314_2325)/p.A775_G776insYVMA
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger cDNA sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [7]

• Molecule Alteration: Complex-indel; p.G776_776delinsVC (c.2326_2328delinsGTATGT)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger cDNA sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [7]

• Molecule Alteration: Duplication; p.G778_P780 (c.2332_2340)/p.780_Y781insGSP
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger cDNA sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Pancreatic cancer [ICD-11: 2C10]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-124 [8]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• 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: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: Capan-1 cells; Pancreas; Homo sapiens (Human); CVCL_0237
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-124 overexpression was able to sensitize the response of Capan-1 cells to erlotinib through inhibiting EphA2.

Key Molecule: hsa-mir-497 [9]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: SW1990 cells; Pancreas; Homo sapiens (Human); CVCL_1723
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-497 suppressed cells proliferation, decreased the percentage of S phase cells, re-sensitized cells to gemcitabine and erlotinib, and attenuated migration and invasion capacities. Furthermore, fibroblast growth factor 2 and fibroblast growth factor receptor 1 were confirmed as miR-497 targets. Overexpression of miR-497 inhibited tumor growth in vivo. Additionally, miR-497 expression was significantly downregulated in pancreatic cancer tissues compared with tumor-adjacent samples. Low expression of miR-497 was an independent adverse prognostic factor of pancreatic cancer. miR-497 plays a role in modulating the malignant phenotype and chemosensitivity of pancreatic cancer cells by directly inhibition of FGF2 and FGFR1 expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ephrin type-A receptor 2 (EPHA2) [8]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• 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: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: Capan-1 cells; Pancreas; Homo sapiens (Human); CVCL_0237
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-124 overexpression was able to sensitize the response of Capan-1 cells to erlotinib through inhibiting EphA2.

Key Molecule: Fibroblast growth factor 2 (FGF1) [9]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: SW1990 cells; Pancreas; Homo sapiens (Human); CVCL_1723
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-497 suppressed cells proliferation, decreased the percentage of S phase cells, re-sensitized cells to gemcitabine and erlotinib, and attenuated migration and invasion capacities. Furthermore, fibroblast growth factor 2 and fibroblast growth factor receptor 1 were confirmed as miR-497 targets. Overexpression of miR-497 inhibited tumor growth in vivo. Additionally, miR-497 expression was significantly downregulated in pancreatic cancer tissues compared with tumor-adjacent samples. Low expression of miR-497 was an independent adverse prognostic factor of pancreatic cancer. miR-497 plays a role in modulating the malignant phenotype and chemosensitivity of pancreatic cancer cells by directly inhibition of FGF2 and FGFR1 expression.

Key Molecule: Fibroblast growth factor receptor 1 (FGFR1) [9]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: SW1990 cells; Pancreas; Homo sapiens (Human); CVCL_1723
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-497 suppressed cells proliferation, decreased the percentage of S phase cells, re-sensitized cells to gemcitabine and erlotinib, and attenuated migration and invasion capacities. Furthermore, fibroblast growth factor 2 and fibroblast growth factor receptor 1 were confirmed as miR-497 targets. Overexpression of miR-497 inhibited tumor growth in vivo. Additionally, miR-497 expression was significantly downregulated in pancreatic cancer tissues compared with tumor-adjacent samples. Low expression of miR-497 was an independent adverse prognostic factor of pancreatic cancer. miR-497 plays a role in modulating the malignant phenotype and chemosensitivity of pancreatic cancer cells by directly inhibition of FGF2 and FGFR1 expression.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [3], [4], [5]

• Molecule Alteration: Missense mutation; p.T790M
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Overall and disease-free assay
• Mechanism Description: Among patients with acquired resistance to EGFR TkIs, the presence of T790M defines a clinical subset with a relatively favorable prognosis and more indolent progression.

Key Molecule: Epidermal growth factor receptor (EGFR) [10], [11]

• Molecule Alteration: Missense mutation; p.T790M
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Computed tomography assay
• Mechanism Description: In addition, three (8%) patients acquired EGFR amplifications in their resistant specimens, all of which also acquired the classic T790M EGFR mutation. Moreover, in two cases with high-level EGFR amplification (>10-fold), it was clear by comparison of the peak heights on the SNaPshot chromatogram that the T790M allele was the amplified allele. They have identified several resistance mechanisms, two of which-EGFR mutation T790M and MET amplification have been validated in the clinic.

Key Molecule: Epidermal growth factor receptor (EGFR) [12]

• Molecule Alteration: Missense mutation; p.C797S+p.T790M
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• 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
• 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) [13]

• Molecule Alteration: Missense mutation; p.D761Y
• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• 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) [13]

• Molecule Alteration: Missense mutation; p.L747S
• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• 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) [13]

• Molecule Alteration: Missense mutation; p.T790M
• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• 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) [14]

• Molecule Alteration: Missense mutation; p.T790M
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• 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) [15]

• Molecule Alteration: Missense mutation; p.T790M
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: H2170 cells; Lung; Homo sapiens (Human); CVCL_1535
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: MTT cell viability assay
• Mechanism Description: H1975 cells are positive for the T790M EGFR mutation, which confers resistance to current EGFR TkI therapies.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-1183 [1]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• 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 [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• 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-223 [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Notch/miR223/FBXW7 signaling pathway; Regulation; hsa04330
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HCC827/ER cells; Lung; Homo sapiens (Human); CVCL_EJ07
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometric apoptosis assay
• Mechanism Description: Sensitivity of non-small cell lung cancer to erlotinib is regulated by the Notch/miR223/FBXW7 pathway. Blocking either the Akt or Notch signaling pathway and reducing miR223 expression resulted in decreased resistance in HCC827/ER cells, miR223 enhanced resistance to erlotinib by down-regulating FBXW7 expression.

Key Molecule: hsa-miR-17-5p [16]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells, miR17-5p could inhibit the mRNA and protein levels of EZH1.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Forkhead box protein O1 (FOXO1) [17]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: HCC4006 cells; Lung; Homo sapiens (Human); CVCL_1269
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA RP11-838N2.4 is required for the erlotinib resistance of NSCLC cells and FOXO1 could bind to the promoter region of LncRNA RP11 838N2.4, resulting in its silencing through the recruitment of histone deacetylase.

Key Molecule: Long non-protein coding RNA (RP11-838N2.4) [17]

• Molecule Alteration: Deacetylation; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: HCC4006 cells; Lung; Homo sapiens (Human); CVCL_1269
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA RP11-838N2.4 is required for the erlotinib resistance of NSCLC cells and FOXO1 could bind to the promoter region of LncRNA RP11 838N2.4, resulting in its silencing through the recruitment of histone deacetylase.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: phosphoinositide-3-dependent protein kinase 1 (PDPK1) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• 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: F-box/WD repeat-containing protein 7 (FBXW7) [6]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Notch/miR223/FBXW7 signaling pathway; Regulation; hsa04330
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HCC827/ER cells; Lung; Homo sapiens (Human); CVCL_EJ07
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometric apoptosis assay
• Mechanism Description: Sensitivity of non-small cell lung cancer to erlotinib is regulated by the Notch/miR223/FBXW7 pathway. Blocking either the Akt or Notch signaling pathway and reducing miR223 expression resulted in decreased resistance in HCC827/ER cells, miR223 enhanced resistance to erlotinib by down-regulating FBXW7 expression.

Key Molecule: Histone-lysine N-methyltransferase EZH1 (EZH1) [16]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells, miR17-5p could inhibit the mRNA and protein levels of EZH1.

Key Molecule: Hepatocyte growth factor receptor (MET) [18]

• Molecule Alteration: Structural variation; Amplification
• Resistant Disease: EGFR-mutant lung adenocarcinoma [ICD-11: 2C25.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MET signaling pathway; Activation; hsa04150
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Fluorescence in situ hybridization assay
• Experiment for Drug Resistance: Computed tomography assay
• Mechanism Description: These two cases already had MET amplification before EGFR-TkI treatment. In contrast, our patient had an EGFR mutation and then newly developed MET amplification after erlotinib therapy, suggesting that MET amplification occurred as a mechanism of acquired resistance.

Key Molecule: PI3-kinase alpha (PIK3CA) [13]

• Molecule Alteration: Mutation; .
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• 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) [13]

• Molecule Alteration: Structural variation; Copy number gain
• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• 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) [13]

• Molecule Alteration: Structural variation; Copy number gain
• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• 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) [13]

• Molecule Alteration: Mutation; .
• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• 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) [13]

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

Key Molecule: PI3-kinase alpha (PIK3CA) [14]

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

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-23a [19]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• 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: PTEN/PI3K/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Inhibition of miR23a increases the sensitivity of lung cancer stem cells to erlotinib through PTEN/PI3k/Akt pathway. Transfection with miR23a inhibitors promoted the erlotinib-dependent inhibition of PI3k/AkT pathway, thus, suppressing the proliferation and inducing apoptosis in PC9 CSCs.

Key Molecule: hsa-mir-214 [20]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: HCC827/ER cells; Lung; Homo sapiens (Human); CVCL_EJ07
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Transwell invasion assay; MTS assay
• Mechanism Description: Down-regulation of miR214 reverses erlotinib resistance in non-small-cell lung cancer through up-regulating LHX6 expression.

Key Molecule: hsa-miR-30a-5p [21]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• 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-223 [22]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• 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 proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF-1R/AKT/S6 signaling pathway; Regulation; hsa05226
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-223 inhibits IGF-1R/Akt/S6 signaling, and this effect is reversed by the exogenous expression of IGF-1. Overexpression of miR-223 enhances the sensitivity of PC-9/ER cells to erlotinib by inducing apoptosis.

Key Molecule: hsa-mir-34 [23]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• 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: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: AlamarBlue assay
• Mechanism Description: A majority of NSCLC and other cancers previously not suited for erlotinib may prove sensitive to the drug when used in combination with a miR-34a-based therapy.

Key Molecule: hsa-let-7c [24]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Inhibition; hsa04340
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-200b and let-7c, inhibited the TGF-beta1-mediated resistance of NSCLC cells to erlotinib.

Key Molecule: hsa-mir-200b [24]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Inhibition; hsa04340
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-200b and let-7c, inhibited the TGF-beta1-mediated resistance of NSCLC cells to erlotinib.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: ERBB receptor feedback inhibitor 1 (ERRFI1) [25]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• 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: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Key Molecule: hsa-mir-200a [25]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• 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: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; RT-PCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Key Molecule: hsa-mir-200b [25]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• 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: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; RT-PCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Key Molecule: hsa-mir-200c [25]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• 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: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; RT-PCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [19]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• 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: PTEN/PI3K/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Inhibition of miR23a increases the sensitivity of lung cancer stem cells to erlotinib through PTEN/PI3k/Akt pathway. Transfection with miR23a inhibitors promoted the erlotinib-dependent inhibition of PI3k/AkT pathway, thus, suppressing the proliferation and inducing apoptosis in PC9 CSCs.

Key Molecule: LIM/homeobox protein Lhx6 (LHX6) [20]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: HCC827/ER cells; Lung; Homo sapiens (Human); CVCL_EJ07
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Transwell invasion assay; MTS assay
• Mechanism Description: Down-regulation of miR214 reverses erlotinib resistance in non-small-cell lung cancer through up-regulating LHX6 expression.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [22]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• 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 proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF-1R/AKT/S6 signaling pathway; Regulation; hsa05226
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-223 inhibits IGF-1R/Akt/S6 signaling, and this effect is reversed by the exogenous expression of IGF-1. Overexpression of miR-223 enhances the sensitivity of PC-9/ER cells to erlotinib by inducing apoptosis.

Bladder cancer [ICD-11: 2C94]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: ERBB receptor feedback inhibitor 1 (ERRFI1) [25]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• 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: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Key Molecule: hsa-mir-200a [25]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• 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: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; RT-PCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Key Molecule: hsa-mir-200b [25]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• 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: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; RT-PCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Key Molecule: hsa-mir-200c [25]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• 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: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; RT-PCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Head and neck cancer [ICD-11: 2D42]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-34 [26]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Head and neck cancer [ICD-11: 2D42.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: HN5 cells; Neck; Homo sapiens (Human); CVCL_8128
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Expression of the tumor suppressor miR-34a was reduced in HN5-ER cells and increasing its expression abrogated Axl expression and reversed erlotinib resistance.

ICD-05: Endocrine/nutritional/metabolic diseases

Lactic acidosis [ICD-11: 5C73]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein kinase C (PRKC) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lactic acidosis [ICD-11: 5C73.Z]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The resistance might occur by several mechanisms, including epigenetic regulation, drug target alteration, multidrug resistance, cancer cell metabolic alteration, or TME factors.

Key Molecule: Protein kinase C (PRKC) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lactic acidosis [ICD-11: 5C73.Z]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The resistance might occur by several mechanisms, including epigenetic regulation, drug target alteration, multidrug resistance, cancer cell metabolic alteration, or TME factors.

References

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