Drug Information

Drug (ID: DG00340) and It's Reported Resistant Information

• Name: Cetuximab
• Synonyms: Erbitux; Cetuximab (genetical recombination); Erbitux (TN); Cetuximab (USAN/INN); Cetuximab (genetical recombination) (JAN); novel EGFR mAb inhibitors
• Indication:
  In total 1 Indication(s)
  Colorectal cancer [ICD-11: 2B91]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Colorectal cancer [ICD-11: 2B91]; [2]
  Metastatic colorectal cancer [ICD-11: 2D85]; [3]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Colorectal cancer [ICD-11: 2B91]; [4]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (3 diseases)
  Colon cancer [ICD-11: 2B90]; [5]
  Colorectal cancer [ICD-11: 2B91]; [6]
  Head and neck cancer [ICD-11: 2D42]; [7]
• Target: Epidermal growth factor receptor (EGFR); EGFR_HUMAN; [1]
• TTD Drug ID: D0N5OV
• DrugBank ID: DB00002

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

Oral squamous cell carcinoma [ICD-11: 2B6E]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa_circ_0005379 [1]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• 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: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Upregualtion of hsa_circ_0005379 enhances the sensitivity of OSCC to anticancer drug cetuximab.

Colon cancer [ICD-11: 2B90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-199a-5p [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: GEO CR cells; Colon; Homo sapiens (Human); CVCL_0271
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AkT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.

Key Molecule: hsa-mir-375 [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: GEO CR cells; Colon; Homo sapiens (Human); CVCL_0271
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AkT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1) [5]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: GEO CR cells; Colon; Homo sapiens (Human); CVCL_0271
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AkT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-143 [8]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• 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: EGFR/RAS/MAPK signaling pathway; Regulation; hsa01521
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The extent of caspase and nuclear fragmentation inhibition was higher in cells overexpressing miR-143 or miR-145, which also display reduced Bcl-2 protein steady-state levels. restoration of miR-143 or miR-145 reduces the aggressiveness of mutant kRAS HCT116 cells. In addition, forced expression of these miRNAs in both mutant and wild-type kRAS colon cancer cells increased their sensitivity to cetuximab by increasing cetuximab-mediated ADCC. Moreover, increased levels of effector cell-mediated caspase-dependent apoptosis were observed for mutant kRAS HCT116 miRNAs-overexpressing cells.

Key Molecule: hsa-mir-145 [8]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• 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: EGFR/RAS/MAPK signaling pathway; Regulation; hsa01521
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The extent of caspase and nuclear fragmentation inhibition was higher in cells overexpressing miR-143 or miR-145, which also display reduced Bcl-2 protein steady-state levels. restoration of miR-143 or miR-145 reduces the aggressiveness of mutant kRAS HCT116 cells. In addition, forced expression of these miRNAs in both mutant and wild-type kRAS colon cancer cells increased their sensitivity to cetuximab by increasing cetuximab-mediated ADCC. Moreover, increased levels of effector cell-mediated caspase-dependent apoptosis were observed for mutant kRAS HCT116 miRNAs-overexpressing cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [8]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• 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: EGFR/RAS/MAPK signaling pathway; Regulation; hsa01521
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The extent of caspase and nuclear fragmentation inhibition was higher in cells overexpressing miR-143 or miR-145, which also display reduced Bcl-2 protein steady-state levels. restoration of miR-143 or miR-145 reduces the aggressiveness of mutant kRAS HCT116 cells. In addition, forced expression of these miRNAs in both mutant and wild-type kRAS colon cancer cells increased their sensitivity to cetuximab by increasing cetuximab-mediated ADCC. Moreover, increased levels of effector cell-mediated caspase-dependent apoptosis were observed for mutant kRAS HCT116 miRNAs-overexpressing cells.

Colorectal cancer [ICD-11: 2B91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [9]

• Molecule Alteration: Missense mutation; p.G465E
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Colon cells; Colon; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy assay
• Mechanism Description: Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: POU class 5 homeobox 1 pseudogene 4 (POU5F1P4) [10]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Down-regulation of POU5F1P4 decreased the sensitivity of colorectal cancer cells to cetuximab. POU5F1P4 may contribute to cetuximab resistance by interacting with protein coding genes that affect different biological pathways.

Key Molecule: Mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: COLO 320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SW948 cells; Colon; Homo sapiens (Human); CVCL_0632
• In Vitro Model: SW403 cells; Colon; Homo sapiens (Human); CVCL_0545
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: LS123 cells; Colon; Homo sapiens (Human); CVCL_1383
• In Vitro Model: SK-CO-1 cells; Colon; Homo sapiens (Human); CVCL_0626
• In Vitro Model: SW837 cells; Colon; Homo sapiens (Human); CVCL_1729
• In Vitro Model: T84 cells; Colon; Homo sapiens (Human); CVCL_0555
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; Sequencing assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: There is a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR125b targeting of GATA6.

Key Molecule: hsa-mir-100 [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: COLO 320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SW948 cells; Colon; Homo sapiens (Human); CVCL_0632
• In Vitro Model: SW403 cells; Colon; Homo sapiens (Human); CVCL_0545
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: LS123 cells; Colon; Homo sapiens (Human); CVCL_1383
• In Vitro Model: SK-CO-1 cells; Colon; Homo sapiens (Human); CVCL_0626
• In Vitro Model: SW837 cells; Colon; Homo sapiens (Human); CVCL_1729
• In Vitro Model: T84 cells; Colon; Homo sapiens (Human); CVCL_0555
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR100 and miR125b coordinately repressed five Wnt/beta-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness.

Key Molecule: hsa-mir-125b [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: COLO 320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SW948 cells; Colon; Homo sapiens (Human); CVCL_0632
• In Vitro Model: SW403 cells; Colon; Homo sapiens (Human); CVCL_0545
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: LS123 cells; Colon; Homo sapiens (Human); CVCL_1383
• In Vitro Model: SK-CO-1 cells; Colon; Homo sapiens (Human); CVCL_0626
• In Vitro Model: SW837 cells; Colon; Homo sapiens (Human); CVCL_1729
• In Vitro Model: T84 cells; Colon; Homo sapiens (Human); CVCL_0555
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR100 and miR125b coordinately repressed five Wnt/beta-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness.

Key Molecule: Mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: CAL62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vitro Model: CAL-62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vitro Model: CCL-131 cells; Brain; Mus musculus (Mouse); CVCL_0470
• In Vitro Model: COLO320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vitro Model: CT26 WT cells; Colon; Mus musculus (Mouse); CVCL_7256
• In Vitro Model: Detroit562 cells; Pleural effusion; Homo sapiens (Human); CVCL_1171
• In Vitro Model: DIPG 007 cells; Brain; Homo sapiens (Human); CVCL_VU70
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: FL83B cells; Liver; Mus musculus (Mouse); CVCL_4691
• In Vitro Model: GH3 cells; Pituitary gland; Rattus norvegicus (Rat); CVCL_0273
• In Vitro Model: GH4C1 cells; pituitary gland; Rattus norvegicus (Rat); CVCL_0276
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: H9 cells; Peripheral blood; Homo sapiens (Human); CVCL_1240
• In Vitro Model: H9/HTLV cells; Peripheral blood; Homo sapiens (Human); CVCL_3514
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HeLa S cells; Uterus; Homo sapiens (Human); CVCL_0058
• In Vitro Model: HeLa229 cells; Uterus; Homo sapiens (Human); CVCL_1276
• In Vitro Model: HH cells; Peripheral blood; Homo sapiens (Human); CVCL_1280
• In Vitro Model: HPrEC cells; Prostate; Homo sapiens (Human); CVCL_A2EM
• In Vitro Model: Human RPMI8226 myeloma cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: KB-C2 cells; Uterus; Homo sapiens (Human); CVCL_D600
• Experiment for Molecule Alteration: RT-PCR
• Mechanism Description: miR-100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/beta-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness.

Key Molecule: hsa-mir-100 [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: CAL62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vitro Model: CAL-62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vitro Model: CCL-131 cells; Brain; Mus musculus (Mouse); CVCL_0470
• In Vitro Model: COLO320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vitro Model: CT26 WT cells; Colon; Mus musculus (Mouse); CVCL_7256
• In Vitro Model: Detroit562 cells; Pleural effusion; Homo sapiens (Human); CVCL_1171
• In Vitro Model: DIPG 007 cells; Brain; Homo sapiens (Human); CVCL_VU70
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: FL83B cells; Liver; Mus musculus (Mouse); CVCL_4691
• In Vitro Model: GH3 cells; Pituitary gland; Rattus norvegicus (Rat); CVCL_0273
• In Vitro Model: GH4C1 cells; pituitary gland; Rattus norvegicus (Rat); CVCL_0276
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: H9 cells; Peripheral blood; Homo sapiens (Human); CVCL_1240
• In Vitro Model: H9/HTLV cells; Peripheral blood; Homo sapiens (Human); CVCL_3514
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HeLa S cells; Uterus; Homo sapiens (Human); CVCL_0058
• In Vitro Model: HeLa229 cells; Uterus; Homo sapiens (Human); CVCL_1276
• In Vitro Model: HH cells; Peripheral blood; Homo sapiens (Human); CVCL_1280
• In Vitro Model: HPrEC cells; Prostate; Homo sapiens (Human); CVCL_A2EM
• In Vitro Model: Human RPMI8226 myeloma cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: KB-C2 cells; Uterus; Homo sapiens (Human); CVCL_D600
• Experiment for Molecule Alteration: RT-PCR
• Mechanism Description: miR-100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/beta-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness.

Key Molecule: hsa-mir-125b [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: GIST-T1 cells; Gastric; Homo sapiens (Human); CVCL_4976
• In Vitro Model: CAL62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vitro Model: CAL-62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vitro Model: CCL-131 cells; Brain; Mus musculus (Mouse); CVCL_0470
• In Vitro Model: COLO320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vitro Model: CT26 WT cells; Colon; Mus musculus (Mouse); CVCL_7256
• In Vitro Model: Detroit562 cells; Pleural effusion; Homo sapiens (Human); CVCL_1171
• In Vitro Model: DIPG 007 cells; Brain; Homo sapiens (Human); CVCL_VU70
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: FL83B cells; Liver; Mus musculus (Mouse); CVCL_4691
• In Vitro Model: GH3 cells; Pituitary gland; Rattus norvegicus (Rat); CVCL_0273
• In Vitro Model: GH4C1 cells; pituitary gland; Rattus norvegicus (Rat); CVCL_0276
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: H9 cells; Peripheral blood; Homo sapiens (Human); CVCL_1240
• In Vitro Model: H9/HTLV cells; Peripheral blood; Homo sapiens (Human); CVCL_3514
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HeLa S cells; Uterus; Homo sapiens (Human); CVCL_0058
• In Vitro Model: HeLa229 cells; Uterus; Homo sapiens (Human); CVCL_1276
• In Vitro Model: HH cells; Peripheral blood; Homo sapiens (Human); CVCL_1280
• In Vitro Model: HPrEC cells; Prostate; Homo sapiens (Human); CVCL_A2EM
• In Vitro Model: Human RPMI8226 myeloma cells; Peripheral blood; Homo sapiens (Human); CVCL_0014
• In Vitro Model: KB-C2 cells; Uterus; Homo sapiens (Human); CVCL_D600
• Experiment for Molecule Alteration: RT-PCR
• Mechanism Description: miR-100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/beta-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Programmed cell death 6-interacting protein (PDCD6IP) [11]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: UCA1 expression was markedly higher in cetuximab-resistant cancer cells and their exosomes and the expression of TSG101, Alix, and CD81, which are all exosome markers and are associated with exosome formation, in both exosomes and cells.

Key Molecule: Urothelial cancer associated 1 (UCA1) [11]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• 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 proliferation; Activation; hsa05200
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: UCA1 expression was markedly higher in cetuximab-resistant cancer cells and their exosomes and the expression of TSG101, Alix, and CD81, which are all exosome markers and are associated with exosome formation, in both exosomes and cells.

Key Molecule: GDH/6PGL endoplasmic bifunctional protein (H6PD) [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Pentose phosphate signaling pathway; Activation; hsa00030
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• In Vivo Model: Xenografts mouse model; Mus musculus
• Experiment for Molecule Alteration: 2D DIGE assay
• Mechanism Description: LDHB and PDHA1 were downregulated in GEO-CR tumor xenografts, similarly to the corresponding deregulations observed in the derived cell lines. Upregulation of G6PDH and transketolase (TkT) was also actually maintained in tumor xenografts. Indeed, PPP2CA expression in xenografted samples was similarly evaluated, demonstrating that protein downregulation in vivo was even more pronounced than that measured in GEO-CR cells.

Key Molecule: L-lactate dehydrogenase B chain (LDHB) [4]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Pentose phosphate signaling pathway; Activation; hsa00030
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• In Vivo Model: Xenografts mouse model; Mus musculus
• Experiment for Molecule Alteration: 2D DIGE assay
• Mechanism Description: LDHB and PDHA1 were downregulated in GEO-CR tumor xenografts, similarly to the corresponding deregulations observed in the derived cell lines. Upregulation of G6PDH and transketolase (TkT) was also actually maintained in tumor xenografts. Indeed, PPP2CA expression in xenografted samples was similarly evaluated, demonstrating that protein downregulation in vivo was even more pronounced than that measured in GEO-CR cells.

Key Molecule: Pyruvate dehydrogenase E1 component subunit alpha (PDHA1) [4]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Pentose phosphate signaling pathway; Activation; hsa00030
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• In Vivo Model: Xenografts mouse model; Mus musculus
• Experiment for Molecule Alteration: 2D DIGE assay
• Mechanism Description: LDHB and PDHA1 were downregulated in GEO-CR tumor xenografts, similarly to the corresponding deregulations observed in the derived cell lines. Upregulation of G6PDH and transketolase (TkT) was also actually maintained in tumor xenografts. Indeed, PPP2CA expression in xenografted samples was similarly evaluated, demonstrating that protein downregulation in vivo was even more pronounced than that measured in GEO-CR cells.

Key Molecule: Transketolase (TKT) [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Pentose phosphate signaling pathway; Activation; hsa00030
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• In Vivo Model: Xenografts mouse model; Mus musculus
• Experiment for Molecule Alteration: 2D DIGE assay
• Mechanism Description: LDHB and PDHA1 were downregulated in GEO-CR tumor xenografts, similarly to the corresponding deregulations observed in the derived cell lines. Upregulation of G6PDH and transketolase (TkT) was also actually maintained in tumor xenografts. Indeed, PPP2CA expression in xenografted samples was similarly evaluated, demonstrating that protein downregulation in vivo was even more pronounced than that measured in GEO-CR cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transcription factor GATA6 (GATA6) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Chemoresistance; Activation; hsa05207
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: COLO 320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SW948 cells; Colon; Homo sapiens (Human); CVCL_0632
• In Vitro Model: SW403 cells; Colon; Homo sapiens (Human); CVCL_0545
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: LS123 cells; Colon; Homo sapiens (Human); CVCL_1383
• In Vitro Model: SK-CO-1 cells; Colon; Homo sapiens (Human); CVCL_0626
• In Vitro Model: SW837 cells; Colon; Homo sapiens (Human); CVCL_1729
• In Vitro Model: T84 cells; Colon; Homo sapiens (Human); CVCL_0555
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; Sequencing assay; Western blot analysis; Immunofluorescent staining assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: There is a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR125b targeting of GATA6.

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [9]

• Molecule Alteration: Missense mutation; p.V600E
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Colon cells; Colon; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy assay
• Mechanism Description: Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: Hepatocyte growth factor receptor (MET) [9]

• Molecule Alteration: Structural variation; Amplification
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• 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: Liquid biopsy assay
• Mechanism Description: Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: GTPase KRas (KRAS) [9]

• Molecule Alteration: Structural variation; Amplification
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• 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: Liquid biopsy assay
• Mechanism Description: Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [9]

• Molecule Alteration: Structural variation; Amplification
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• 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: Liquid biopsy assay
• Mechanism Description: Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: GTPase KRas (KRAS) [9]

• Molecule Alteration: Missense mutation; p.Q61H
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• 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: Liquid biopsy assay
• Mechanism Description: Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: GTPase KRas (KRAS) [9], [12], [13]

• Molecule Alteration: Missense mutation; p.G12V
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR/RAS signaling pathway; Activation; hsa01521
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy assay
• Mechanism Description: Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations (27780856). kRAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs).

Key Molecule: GTPase KRas (KRAS) [9]

• Molecule Alteration: Missense mutation; p.G12D
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• 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: Liquid biopsy assay
• Mechanism Description: Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: Hepatocyte growth factor receptor (MET) [2]

• Molecule Alteration: Structural variation; Copy number gain
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• 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 analysis; Gene copy number analysis
• Mechanism Description: As amplification of the MET gene has recently been shown to drive resistance to anti-EGFR therapies, this copy number change is the best candidate to explain the poor treatment response.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [14]

• Molecule Alteration: Structural variation; Amplification
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Mechanism Description: Mutations in kRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment.

Key Molecule: GTPase KRas (KRAS) [15]

• Molecule Alteration: Mutation; Mutations in codons 12, 13 and 61
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAS/RAF/Mek/ERK signaling pathway; Activation; hsa04010
• In Vitro Model: Colorectal cancer cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: High throughout experiment assay
• Experiment for Drug Resistance: Circulating tumor DNA analysis
• Mechanism Description: The identification of kRAS mutations as a cause for intrinsic resistance of colorectal cancers also contributed to the identification of a mechanism for the acquired resistance. Establishment and analysis of cetuximabresistant colorectal cancer cell lines revealed that the resistant variants harbored kRAS point mutations or amplification, and the findings were confirmed in clinical specimens.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-7 [16]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Epidermal growth factor receptor (EGFR) [16]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation.

Key Molecule: RAF proto-oncogene serine/threonine-protein kinase (RAF1) [16]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation.

Liver cancer [ICD-11: 2C12]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-let-7a [17]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by negatively regulating STAT3 expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Signal transducer activator transcription 3 (STAT3) [17]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by negatively regulating STAT3 expression.

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-200c [18]

• 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 invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• 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 Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H522 cells; Lung; Homo sapiens (Human); CVCL_1567
• In Vitro Model: NCl-H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: Calu1 cells; Lung; Homo sapiens (Human); CVCL_0608
• In Vitro Model: NCI-H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• Experiment for Molecule Alteration: Methylation-specific PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Reintroduction of miR-200c into highly invasive/aggressive NSCLC cells induced a loss of the mesenchymal phenotype by restoring E-cadherin and reducing N-cadherin expression, and inhibited in vitro cell invasion as well as in vivo metastasis formation.

Bladder cancer [ICD-11: 2C94]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-200b [19]

• 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: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: 253J BV cells; Bladder; Homo sapiens (Human); CVCL_7937
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Pulse-labeling cells with [3H]thymidine
• Mechanism Description: Members of the miR-200 family appear to control the EMT process and sensitivity to EGFR therapy, in bladder cancer cells and that expression of miR-200 is sufficient to restore EGFR dependency, at least in some of the mesenchymal bladder cancer cells. The targets of miR-200 include ERRFI-1, which is a novel regulator of EGFR-independent growth.

Key Molecule: hsa-mir-200c [19]

• 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: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: 253J BV cells; Bladder; Homo sapiens (Human); CVCL_7937
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Pulse-labeling cells with [3H]thymidine
• Mechanism Description: Members of the miR-200 family appear to control the EMT process and sensitivity to EGFR therapy, in bladder cancer cells and that expression of miR-200 is sufficient to restore EGFR dependency, at least in some of the mesenchymal bladder cancer cells. The targets of miR-200 include ERRFI-1, which is a novel regulator of EGFR-independent growth.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: ERBB receptor feedback inhibitor 1 (ERRFI1) [19]

• 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: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: 253J BV cells; Bladder; Homo sapiens (Human); CVCL_7937
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Pulse-labeling cells with [3H]thymidine
• Mechanism Description: Members of the miR-200 family appear to control the EMT process and sensitivity to EGFR therapy, in bladder cancer cells and that expression of miR-200 is sufficient to restore EGFR dependency, at least in some of the mesenchymal bladder cancer cells. The targets of miR-200 include ERRFI-1, which is a novel regulator of EGFR-independent growth.

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-212 [7]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SCC1 cells; Tongue; Homo sapiens (Human); CVCL_A5SA
• In Vitro Model: 1Cc8 cells; Epithelium; Homo sapiens (Human); CVCL_L893
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: HB-EGF can induce EMT, enhance metastasis, and modulate chemotherapy resistance. Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proheparin-binding EGF-like growth factor (HBEGF) [7]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SCC1 cells; Tongue; Homo sapiens (Human); CVCL_A5SA
• In Vitro Model: 1Cc8 cells; Epithelium; Homo sapiens (Human); CVCL_L893
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: HB-EGF can induce EMT, enhance metastasis, and modulate chemotherapy resistance. Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-204 [20]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Inhibition; hsa04030
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR204 inhibits angiogenesis and promotes sensitivity to cetuximab in head and neck squamous cell carcinoma cells by blocking JAk2-STAT3 signaling.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [20]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Inhibition; hsa04030
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR204 inhibits angiogenesis and promotes sensitivity to cetuximab in head and neck squamous cell carcinoma cells by blocking JAk2-STAT3 signaling.

Metastatic colorectal cancer [ICD-11: 2D85]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [13]

• Molecule Alteration: Missense mutation; p.S492R
• Resistant Disease: Metastatic colorectal cancer [ICD-11: 2D85.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Standard-of-care sequencing assay
• Mechanism Description: K-RAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase KRas (KRAS) [3]

• Molecule Alteration: Missense mutation; p.Q61H
• Resistant Disease: Metastatic colorectal cancer [ICD-11: 2D85.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: DiFi cells; Colon; Homo sapiens (Human); CVCL_6895
• In Vitro Model: DiFi-R cells; Colon; Homo sapiens (Human); CVCL_A2BW
• In Vitro Model: Lim1215-R cells; Colon; Homo sapiens (Human); CVCL_1736
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: FISH analysis; Sanger sequencing assay
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Nevertheless, our functional analysis in cell models show that kRAS mutations are causally responsible for acquired resistance to cetuximab.

Key Molecule: GTPase Nras (NRAS) [21]

• Molecule Alteration: Missense mutation; p.G12C
• Resistant Disease: Metastatic colorectal cancer [ICD-11: 2D85.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR/RAS signaling pathway; Inhibition; hsa01521
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• 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 biopsies assay; Functional analyses of cell populations assay
• Mechanism Description: Acquired resistance to EGFR blockade is driven by the emergence of kRAS/NRAS mutations or the development of EGFR extracellular domain (ECD) variants, which impair antibody binding.

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

• Molecule Alteration: Structural variation; Copy number gain
• Resistant Disease: Metastatic colorectal cancer [ICD-11: 2D85.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Mechanism Description: Mutations in kRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment.

Key Molecule: GTPase KRas (KRAS) [14]

• Molecule Alteration: Mutation; .
• Resistant Disease: Metastatic colorectal cancer [ICD-11: 2D85.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Mechanism Description: Mutations in kRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment.

References

• Ref 1: Hsa_circ_0005379 regulates malignant behavior of oral squamous cell carcinoma through the EGFR pathway. BMC Cancer. 2019 Apr 29;19(1):400. doi: 10.1186/s12885-019-5593-5.
• Ref 2: Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 2013 Jun;3(6):658-73. doi: 10.1158/2159-8290.CD-12-0558. Epub 2013 Jun 2.
• Ref 3: Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012 Jun 28;486(7404):532-6. doi: 10.1038/nature11156.
• Ref 4: Increased anaerobic metabolism is a distinctive signature in a colorectal cancer cellular model of resistance to antiepidermal growth factor receptor antibody. Proteomics. 2013 Mar;13(5):866-77. doi: 10.1002/pmic.201200303. Epub 2013 Jan 24.
• Ref 5: MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1. Expert Opin Ther Targets. 2015;19(8):1017-26. doi: 10.1517/14728222.2015.1057569. Epub 2015 Jun 24.
• Ref 6: lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/Beta-catenin signaling. Nat Med. 2017 Nov;23(11):1331-1341. doi: 10.1038/nm.4424. Epub 2017 Oct 16.
• Ref 7: Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. PLoS One. 2010 Sep 13;5(9):e12702. doi: 10.1371/journal.pone.0012702.
• Ref 8: miR-143 or miR-145 overexpression increases cetuximab-mediated antibody-dependent cellular cytotoxicity in human colon cancer cells. Oncotarget. 2016 Feb 23;7(8):9368-87. doi: 10.18632/oncotarget.7010.
• Ref 9: Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer. Clin Cancer Res. 2017 May 15;23(10):2414-2422. doi: 10.1158/1078-0432.CCR-16-1863. Epub 2016 Oct 25.
• Ref 10: Identification and validation of cetuximab resistance associated long noncoding RNA biomarkers in metastatic colorectal cancer. Biomed Pharmacother. 2018 Jan;97:1138-1146. doi: 10.1016/j.biopha.2017.11.031. Epub 2017 Nov 10.
• Ref 11: Predictive role of UCA1-containing exosomes in cetuximab-resistant colorectal cancer. Cancer Cell Int. 2018 Oct 22;18:164. doi: 10.1186/s12935-018-0660-6. eCollection 2018.
• Ref 12: 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 13: Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. Ann Oncol. 2015 Apr;26(4):731-736. doi: 10.1093/annonc/mdv005. Epub 2015 Jan 26.
• Ref 14: Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov. 2014 Nov;4(11):1269-80. doi: 10.1158/2159-8290.CD-14-0462. Epub 2014 Oct 7.
• Ref 15: The Moment that KRAS Mutation Started to Evolve into Precision Medicine in Metastatic Colorectal Cancer. Cancer Res. 2016 Nov 15;76(22):6443-6444. doi: 10.1158/0008-5472.CAN-16-2867.
• Ref 16: MicroRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation. Carcinogenesis. 2015 Mar;36(3):338-45. doi: 10.1093/carcin/bgu242. Epub 2014 Dec 10.
• Ref 17: Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by regulating STAT3 expression. Onco Targets Ther. 2016 Nov 28;9:7253-7261. doi: 10.2147/OTT.S116127. eCollection 2016.
• Ref 18: Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer. Mol Cancer Res. 2010 Sep;8(9):1207-16. doi: 10.1158/1541-7786.MCR-10-0052. Epub 2010 Aug 9.
• Ref 19: miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clin Cancer Res. 2009 Aug 15;15(16):5060-72. doi: 10.1158/1078-0432.CCR-08-2245. Epub 2009 Aug 11.
• Ref 20: miR-204 inhibits angiogenesis and promotes sensitivity to cetuximab in head and neck squamous cell carcinoma cells by blocking JAK2-STAT3 signaling. Biomed Pharmacother. 2018 Mar;99:278-285. doi: 10.1016/j.biopha.2018.01.055.
• Ref 21: Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer. Nat Commun. 2016 Dec 8;7:13665. doi: 10.1038/ncomms13665.