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
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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 (3 diseases)
Colorectal cancer [ICD-11: 2B91]
[2]
Head and neck squamous cell carcinoma [ICD-11: 2D60]
[3]
Metastatic colorectal cancer [ICD-11: 2D85]
[4]
Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
Colorectal cancer [ICD-11: 2B91]
[5]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (5 diseases)
Colon cancer [ICD-11: 2B90]
[6]
Colorectal cancer [ICD-11: 2B91]
[7]
Gastric cancer [ICD-11: 2B72]
[8]
Head and neck cancer [ICD-11: 2D42]
[9]
Head and neck squamous cell carcinoma [ICD-11: 2D60]
[3]
Target Epidermal growth factor receptor (EGFR) EGFR_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
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
  MRAP: Metabolic Reprogramming via Altered Pathways
  RTDM: Regulation by the Disease Microenvironment
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
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Head and neck cancer [ICD-11: 2D42]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Proheparin-binding EGF-like growth factor (HBEGF) [9]
Resistant Disease Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Head and neck cancer [ICD-11: 2D42]
The Specified Disease Head and neck cancer
The Studied Tissue Head and neck tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 8.24E-14
Fold-change: 1.52E-01
Z-score: 8.29E+00
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
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.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-212 [9]
Resistant Disease Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
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
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.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-204 [26]
Sensitive Disease Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
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) Click to Show/Hide
Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [26]
Sensitive Disease Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
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
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.
Liver cancer [ICD-11: 2C12]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Signal transducer activator transcription 3 (STAT3) [10]
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Liver cancer [ICD-11: 2C12]
The Specified Disease Liver cancer
The Studied Tissue Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 6.50E-03
Fold-change: -4.36E-02
Z-score: -2.83E+00
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
SNU449 cells Liver Homo sapiens (Human) CVCL_0454
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.
Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [23]
Sensitive Disease Cholangiocarcinoma [ICD-11: 2C12.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation EGF-EGFR signaling pathway Regulation N.A.
In Vivo Model Mouse model Mus musculus
Experiment for
Molecule Alteration		 Immunoprecipitation assay; LC-MS/MS analysis
Experiment for
Drug Resistance		 Cellular ROS and lipid peroxidation level assay; LOXL3 enzymatic assay; In vitro kinase assay
Mechanism Description To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-let-7a [10]
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
SNU449 cells Liver Homo sapiens (Human) CVCL_0454
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.
Colon cancer [ICD-11: 2B90]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1) [6]
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Colon cancer [ICD-11: 2B90]
The Specified Disease Colon cancer
The Studied Tissue Colon tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 7.37E-37
Fold-change: -9.49E-02
Z-score: -1.47E+01
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation AKT signaling pathway Inhibition hsa04151
Cell migration Activation hsa04670
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.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-199a-5p [6]
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation AKT signaling pathway Inhibition hsa04151
Cell migration Activation hsa04670
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 [6]
Resistant Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation AKT signaling pathway Inhibition hsa04151
Cell migration Activation hsa04670
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.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-143 [11]
Sensitive Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
EGFR/RAS/MAPK signaling pathway Regulation N.A.
In Vitro Model SW480 cells Colon Homo sapiens (Human) CVCL_0546
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 [11]
Sensitive Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
EGFR/RAS/MAPK signaling pathway Regulation N.A.
In Vitro Model SW480 cells Colon Homo sapiens (Human) CVCL_0546
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) Click to Show/Hide
Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [11]
Sensitive Disease Colon cancer [ICD-11: 2B90.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
EGFR/RAS/MAPK signaling pathway Regulation N.A.
In Vitro Model SW480 cells Colon Homo sapiens (Human) CVCL_0546
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.
Oral squamous cell carcinoma [ICD-11: 2B6E]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa_circ_0005379 [1]
Sensitive Disease Oral squamous cell carcinoma [ICD-11: 2B6E.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
EGFR signaling pathway Inhibition hsa01521
In Vitro Model CAL27 cells Oral Homo sapiens (Human) CVCL_1107
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.
Gastric cancer [ICD-11: 2B72]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Alanine-serine-cysteine transporter 2 (ASCT2) [8]
Metabolic Type Glutamine metabolism
Resistant Disease Gastric adenocarcinoma [ICD-11: 2B72.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model BGC803 cells Stomach Homo sapiens (Human) CVCL_5334
GES-1 cells Gastric Homo sapiens (Human) CVCL_EQ22
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description The expression of the key glutamine transporter alanine-serine-cysteine (ASC) transporter 2 (ASCT2; SLC1A5) was significantly higher in gastric carcinoma tissues and various gastric carcinoma cell lines than in normal gastric tissues and cells, as shown by immunohistochemistry and western blotting, while silencing ASCT2 significantly inhibited the viability and proliferation of gastric carcinoma cells. Consistent with previous studies, it was shown herein by MTT and EdU assays that cetuximab had a weak inhibitory effect on the cell viability of gastric carcinoma cells. However, inhibiting glutamine uptake by blockade of ASCT2 with l-gamma-glutamyl-p-nitroanilide (GPNA) significantly enhanced the inhibitory effect of cetuximab on suppressing the proliferation of gastric cancer both in vitro and in vivo.
Colorectal cancer [ICD-11: 2B91]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [12]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.G465E
 Molecule Info 
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) Click to Show/Hide
Key Molecule: POU class 5 homeobox 1 pseudogene 4 (POU5F1P4) [13]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model CaCo2 cells Colon Homo sapiens (Human) CVCL_0025
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) [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
SW480 cells Colon Homo sapiens (Human) CVCL_0546
DLD1 cells Colon Homo sapiens (Human) CVCL_0248
SW620 cells Colon Homo sapiens (Human) CVCL_0547
CaCo2 cells Colon Homo sapiens (Human) CVCL_0025
HCT116 cells Colon Homo sapiens (Human) CVCL_0291
LOVO cells Colon Homo sapiens (Human) CVCL_0399
RkO cells Colon Homo sapiens (Human) CVCL_0504
HCT8 cells Colon Homo sapiens (Human) CVCL_2478
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
SW1116 cells Colon Homo sapiens (Human) CVCL_0544
COLO 320DM cells Colon Homo sapiens (Human) CVCL_0219
HCT15 cells Colon Homo sapiens (Human) CVCL_0292
LS174T cells Colon Homo sapiens (Human) CVCL_1384
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
SW948 cells Colon Homo sapiens (Human) CVCL_0632
SW403 cells Colon Homo sapiens (Human) CVCL_0545
SW48 cells Colon Homo sapiens (Human) CVCL_1724
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
HuTu80 cells Small intestine Homo sapiens (Human) CVCL_1301
LS123 cells Colon Homo sapiens (Human) CVCL_1383
SK-CO-1 cells Colon Homo sapiens (Human) CVCL_0626
SW837 cells Colon Homo sapiens (Human) CVCL_1729
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 [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
SW480 cells Colon Homo sapiens (Human) CVCL_0546
DLD1 cells Colon Homo sapiens (Human) CVCL_0248
SW620 cells Colon Homo sapiens (Human) CVCL_0547
CaCo2 cells Colon Homo sapiens (Human) CVCL_0025
HCT116 cells Colon Homo sapiens (Human) CVCL_0291
LOVO cells Colon Homo sapiens (Human) CVCL_0399
RkO cells Colon Homo sapiens (Human) CVCL_0504
HCT8 cells Colon Homo sapiens (Human) CVCL_2478
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
SW1116 cells Colon Homo sapiens (Human) CVCL_0544
COLO 320DM cells Colon Homo sapiens (Human) CVCL_0219
HCT15 cells Colon Homo sapiens (Human) CVCL_0292
LS174T cells Colon Homo sapiens (Human) CVCL_1384
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
SW948 cells Colon Homo sapiens (Human) CVCL_0632
SW403 cells Colon Homo sapiens (Human) CVCL_0545
SW48 cells Colon Homo sapiens (Human) CVCL_1724
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
HuTu80 cells Small intestine Homo sapiens (Human) CVCL_1301
LS123 cells Colon Homo sapiens (Human) CVCL_1383
SK-CO-1 cells Colon Homo sapiens (Human) CVCL_0626
SW837 cells Colon Homo sapiens (Human) CVCL_1729
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 [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
SW480 cells Colon Homo sapiens (Human) CVCL_0546
DLD1 cells Colon Homo sapiens (Human) CVCL_0248
SW620 cells Colon Homo sapiens (Human) CVCL_0547
CaCo2 cells Colon Homo sapiens (Human) CVCL_0025
HCT116 cells Colon Homo sapiens (Human) CVCL_0291
LOVO cells Colon Homo sapiens (Human) CVCL_0399
RkO cells Colon Homo sapiens (Human) CVCL_0504
HCT8 cells Colon Homo sapiens (Human) CVCL_2478
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
SW1116 cells Colon Homo sapiens (Human) CVCL_0544
COLO 320DM cells Colon Homo sapiens (Human) CVCL_0219
HCT15 cells Colon Homo sapiens (Human) CVCL_0292
LS174T cells Colon Homo sapiens (Human) CVCL_1384
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
SW948 cells Colon Homo sapiens (Human) CVCL_0632
SW403 cells Colon Homo sapiens (Human) CVCL_0545
SW48 cells Colon Homo sapiens (Human) CVCL_1724
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
HuTu80 cells Small intestine Homo sapiens (Human) CVCL_1301
LS123 cells Colon Homo sapiens (Human) CVCL_1383
SK-CO-1 cells Colon Homo sapiens (Human) CVCL_0626
SW837 cells Colon Homo sapiens (Human) CVCL_1729
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) [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
CAL62 cells Thyroid gland Homo sapiens (Human) CVCL_1112
CAL-62 cells Thyroid gland Homo sapiens (Human) CVCL_1112
CCL-131 cells Brain Mus musculus (Mouse) CVCL_0470
COLO320DM cells Colon Homo sapiens (Human) CVCL_0219
CT26 WT cells Colon Mus musculus (Mouse) CVCL_7256
Detroit562 cells Pleural effusion Homo sapiens (Human) CVCL_1171
DIPG 007 cells Brain Homo sapiens (Human) CVCL_VU70
DLD-1 cells Colon Homo sapiens (Human) CVCL_0248
DU145 cells Prostate Homo sapiens (Human) CVCL_0105
FL83B cells Liver Mus musculus (Mouse) CVCL_4691
GH3 cells Pituitary gland Rattus norvegicus (Rat) CVCL_0273
GH4C1 cells pituitary gland Rattus norvegicus (Rat) CVCL_0276
H1650 cells Pleural effusion Homo sapiens (Human) CVCL_4V01
H9 cells Peripheral blood Homo sapiens (Human) CVCL_1240
H9/HTLV cells Peripheral blood Homo sapiens (Human) CVCL_3514
HEK 293T cells Kidney Homo sapiens (Human) CVCL_0063
HeLa S cells Uterus Homo sapiens (Human) CVCL_0058
HeLa229 cells Uterus Homo sapiens (Human) CVCL_1276
HH cells Peripheral blood Homo sapiens (Human) CVCL_1280
HPrEC cells Prostate Homo sapiens (Human) CVCL_A2EM
Human RPMI8226 myeloma cells Peripheral blood Homo sapiens (Human) CVCL_0014
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 [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
CAL62 cells Thyroid gland Homo sapiens (Human) CVCL_1112
CAL-62 cells Thyroid gland Homo sapiens (Human) CVCL_1112
CCL-131 cells Brain Mus musculus (Mouse) CVCL_0470
COLO320DM cells Colon Homo sapiens (Human) CVCL_0219
CT26 WT cells Colon Mus musculus (Mouse) CVCL_7256
Detroit562 cells Pleural effusion Homo sapiens (Human) CVCL_1171
DIPG 007 cells Brain Homo sapiens (Human) CVCL_VU70
DLD-1 cells Colon Homo sapiens (Human) CVCL_0248
DU145 cells Prostate Homo sapiens (Human) CVCL_0105
FL83B cells Liver Mus musculus (Mouse) CVCL_4691
GH3 cells Pituitary gland Rattus norvegicus (Rat) CVCL_0273
GH4C1 cells pituitary gland Rattus norvegicus (Rat) CVCL_0276
H1650 cells Pleural effusion Homo sapiens (Human) CVCL_4V01
H9 cells Peripheral blood Homo sapiens (Human) CVCL_1240
H9/HTLV cells Peripheral blood Homo sapiens (Human) CVCL_3514
HEK 293T cells Kidney Homo sapiens (Human) CVCL_0063
HeLa S cells Uterus Homo sapiens (Human) CVCL_0058
HeLa229 cells Uterus Homo sapiens (Human) CVCL_1276
HH cells Peripheral blood Homo sapiens (Human) CVCL_1280
HPrEC cells Prostate Homo sapiens (Human) CVCL_A2EM
Human RPMI8226 myeloma cells Peripheral blood Homo sapiens (Human) CVCL_0014
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 [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
CAL62 cells Thyroid gland Homo sapiens (Human) CVCL_1112
CAL-62 cells Thyroid gland Homo sapiens (Human) CVCL_1112
CCL-131 cells Brain Mus musculus (Mouse) CVCL_0470
COLO320DM cells Colon Homo sapiens (Human) CVCL_0219
CT26 WT cells Colon Mus musculus (Mouse) CVCL_7256
Detroit562 cells Pleural effusion Homo sapiens (Human) CVCL_1171
DIPG 007 cells Brain Homo sapiens (Human) CVCL_VU70
DLD-1 cells Colon Homo sapiens (Human) CVCL_0248
DU145 cells Prostate Homo sapiens (Human) CVCL_0105
FL83B cells Liver Mus musculus (Mouse) CVCL_4691
GH3 cells Pituitary gland Rattus norvegicus (Rat) CVCL_0273
GH4C1 cells pituitary gland Rattus norvegicus (Rat) CVCL_0276
H1650 cells Pleural effusion Homo sapiens (Human) CVCL_4V01
H9 cells Peripheral blood Homo sapiens (Human) CVCL_1240
H9/HTLV cells Peripheral blood Homo sapiens (Human) CVCL_3514
HEK 293T cells Kidney Homo sapiens (Human) CVCL_0063
HeLa S cells Uterus Homo sapiens (Human) CVCL_0058
HeLa229 cells Uterus Homo sapiens (Human) CVCL_1276
HH cells Peripheral blood Homo sapiens (Human) CVCL_1280
HPrEC cells Prostate Homo sapiens (Human) CVCL_A2EM
Human RPMI8226 myeloma cells Peripheral blood Homo sapiens (Human) CVCL_0014
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.
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Tumor necrosis factor receptor-associated protein 1 (TRAP1) [14]
Metabolic Type Glucose metabolism
Resistant Disease Colorectal carcinomas [ICD-11: 2B91.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model Human RAS-wild-type mCRCs Homo Sapiens
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 18F-FDG uptake
Mechanism Description TRAP1 is a determinant of metabolic rewiring in human CRCs by the modulation of PFK1 activity/stability and favors resistance to EGFR inhibitors through the regulation of glycolytic metabolism.
Key Molecule: Tumor necrosis factor receptor-associated protein 1 (TRAP1) [14]
Metabolic Type Glucose metabolism
Resistant Disease Colorectal carcinomas [ICD-11: 2B91.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model Human RAS-wild-type mCRCs Homo Sapiens
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Stable tumors assay
Mechanism Description TRAP1 is a determinant of metabolic rewiring in human CRCs by the modulation of PFK1 activity/stability and favors resistance to EGFR inhibitors through the regulation of glycolytic metabolism.
Key Molecule: Solute carrier family 25 member 21 (SLC25A21) [15]
Metabolic Type Glutamine metabolism
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Caco2 cells Colon Homo sapiens (Human) CVCL_0025
DLD-1 cells Colon Homo sapiens (Human) CVCL_0248
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
LS 174T cells Colon Homo sapiens (Human) CVCL_1384
LOVO cells Colon Homo sapiens (Human) CVCL_0399
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description Restoration of SLC25A21 expression abrogates KRAS-mutation-mediated resistance to cetuximab in CRC. KRAS mutation, which results in hyperactive PI3K/AKT and RAF/ERK signaling (26), is responsible for resistance to anti-EGFR antibody therapy (27).
Key Molecule: Solute carrier family 25 member 21 (SLC25A21) [15]
Metabolic Type Glutamine metabolism
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model M5 cells Colon Homo sapiens (Human) CVCL_WH33
SW620 cells Colon Homo sapiens (Human) CVCL_0547
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description Restoration of SLC25A21 expression abrogates KRAS-mutation-mediated resistance to cetuximab in CRC. KRAS mutation, which results in hyperactive PI3K/AKT and RAF/ERK signaling (26), is responsible for resistance to anti-EGFR antibody therapy (27).
Key Molecule: Tumor necrosis factor receptor-associated protein 1 (TRAP1) [14]
Metabolic Type Glucose metabolism
Resistant Disease Colorectal carcinomas [ICD-11: 2B91.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model RAS-wild-type Caco2 cells Colon Homo sapiens (Human) CVCL_0025
RAS-wild-type NCIH508 cells Colon Homo sapiens (Human) CVCL_1564
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description TRAP1 is a determinant of metabolic rewiring in human CRCs by the modulation of PFK1 activity/stability and favors resistance to EGFR inhibitors through the regulation of glycolytic metabolism.
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: Programmed cell death 6-interacting protein (PDCD6IP) [16]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell colony Activation hsa05200
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
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) [16]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell colony Activation hsa05200
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) [5]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
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) [5]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
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
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) [5]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
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
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) [5]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
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) Click to Show/Hide
Key Molecule: GTPase KRas (KRAS) [12], [17], [18]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.G12V
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.98  Å
PDB: 7SCW
Mutant Type Structure Method: X-ray diffraction Resolution: 1.96  Å
PDB: 7SCX
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.47
TM score: 0.99104
Amino acid change:
G12V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
0
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S
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
V
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
S
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
170
|
M
M
S
S
K
K
D
D
G
G
K
K
K
K
K
K
K
K
K
K
180
|
K
K
S
S
K
K
T
T
K
K
C
C
V
V
I
I
M
M
Click to Show/Hide the Structure
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) [12]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.31  Å
PDB: 6T5V
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6MNX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.14
TM score: 0.96411
Amino acid change:
Q61H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
C
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
S
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
H
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
L
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
C
D
D
120
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L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 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) [12]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 8JHL
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.9318
Amino acid change:
G12D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
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G
G
A
A
G
D
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 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: Serine/threonine-protein kinase B-raf (BRAF) [12]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.V600E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
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: Transcription factor GATA6 (GATA6) [7]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Chemoresistance Activation hsa05207
Wnt/Beta-catenin signaling pathway Inhibition hsa04310
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
SW480 cells Colon Homo sapiens (Human) CVCL_0546
DLD1 cells Colon Homo sapiens (Human) CVCL_0248
SW620 cells Colon Homo sapiens (Human) CVCL_0547
CaCo2 cells Colon Homo sapiens (Human) CVCL_0025
HCT116 cells Colon Homo sapiens (Human) CVCL_0291
LOVO cells Colon Homo sapiens (Human) CVCL_0399
RkO cells Colon Homo sapiens (Human) CVCL_0504
HCT8 cells Colon Homo sapiens (Human) CVCL_2478
NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
SW1116 cells Colon Homo sapiens (Human) CVCL_0544
COLO 320DM cells Colon Homo sapiens (Human) CVCL_0219
HCT15 cells Colon Homo sapiens (Human) CVCL_0292
LS174T cells Colon Homo sapiens (Human) CVCL_1384
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
SW948 cells Colon Homo sapiens (Human) CVCL_0632
SW403 cells Colon Homo sapiens (Human) CVCL_0545
SW48 cells Colon Homo sapiens (Human) CVCL_1724
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
HuTu80 cells Small intestine Homo sapiens (Human) CVCL_1301
LS123 cells Colon Homo sapiens (Human) CVCL_1383
SK-CO-1 cells Colon Homo sapiens (Human) CVCL_0626
SW837 cells Colon Homo sapiens (Human) CVCL_1729
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: Hepatocyte growth factor receptor (MET) [12]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Structural variation
Amplification
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 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) [12]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Structural variation
Amplification
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 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) [12]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Structural variation
Amplification
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 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]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Structural variation
Copy number gain
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing 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) [19]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Structural variation
Amplification
 Molecule Info 
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) [20]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Mutation
Mutations in codons 12, 13 and 61
 Molecule Info 
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.
Key Molecule: Homeobox protein Hox-B8 (HOXB8) [21]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation STAT3 signaling pathway Activation hsa04550
In Vitro Model Caco2 cells Colon Homo sapiens (Human) CVCL_0025
HCT-116 cells Colon Homo sapiens (Human) CVCL_0291
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.
Key Molecule: Signal transducer and activator of transcription 3 (STAT3) [21]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation STAT3 signaling pathway Activation hsa04550
In Vitro Model Caco2 cells Colon Homo sapiens (Human) CVCL_0025
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.
Key Molecule: Signal transducer and activator of transcription 3 (STAT3) [21]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation STAT3 signaling pathway Activation hsa04550
In Vitro Model HCT-116 cells Colon Homo sapiens (Human) CVCL_0291
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-7 [22]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
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
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) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [22]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
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) [22]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
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
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: Homeobox protein Hox-B8 (HOXB8) [21]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation STAT3 signaling pathway Activation hsa04550
In Vitro Model SW48 cells Colon Homo sapiens (Human) CVCL_1724
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.
Key Molecule: Signal transducer and activator of transcription 3 (STAT3) [21]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation STAT3 signaling pathway Activation hsa04550
In Vitro Model SW48 cells Colon Homo sapiens (Human) CVCL_1724
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 MTT assay; Colony formation assay
Mechanism Description By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.
Lung cancer [ICD-11: 2C25]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-200c [24]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell proliferation Inhibition hsa05200
In Vitro Model Calu3 cells Lung Homo sapiens (Human) CVCL_0609
H1299 cells Lung Homo sapiens (Human) CVCL_0060
Sk-MES-1 cells Lung Homo sapiens (Human) CVCL_0630
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H522 cells Lung Homo sapiens (Human) CVCL_1567
NCl-H596 cells Lung Homo sapiens (Human) CVCL_1571
NCI-H520 cells Lung Homo sapiens (Human) CVCL_1566
Calu1 cells Lung Homo sapiens (Human) CVCL_0608
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]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-200b [25]
Sensitive Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation EGFR signaling pathway Regulation N.A.
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 [25]
Sensitive Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation EGFR signaling pathway Regulation N.A.
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) Click to Show/Hide
Key Molecule: ERBB receptor feedback inhibitor 1 (ERRFI1) [25]
Sensitive Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation EGFR signaling pathway Regulation N.A.
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.
Metastatic colorectal cancer [ICD-11: 2D85]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [18]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease Info 
Molecule Alteration Missense mutation
p.S492R
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 3C09
Mutant Type Structure Method: X-ray diffraction Resolution: 2.80  Å
PDB: 6B3S
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.58
TM score: 0.98774
Amino acid change:
S492R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
L
L
E
E
E
E
310
|
K
K
K
K
V
V
C
C
N
N
G
G
I
I
G
G
I
I
G
G
320
|
E
E
F
F
K
K
D
D
S
S
L
L
S
S
I
I
N
N
A
A
330
|
T
T
N
N
I
I
K
K
H
H
F
F
K
K
N
N
C
C
T
T
340
|
S
S
I
I
S
S
G
G
D
D
L
L
H
H
I
I
L
L
P
P
350
|
V
V
A
A
F
F
R
R
G
G
D
D
S
S
F
F
T
T
H
H
360
|
T
T
P
P
P
P
L
L
D
D
P
P
Q
Q
E
E
L
L
D
D
370
|
I
I
L
L
K
K
T
T
V
V
K
K
E
E
I
I
T
T
G
G
380
|
F
F
L
L
L
L
I
I
Q
Q
A
A
W
W
P
P
E
E
N
N
390
|
R
R
T
T
D
D
L
L
H
H
A
A
F
F
E
E
N
N
L
L
400
|
E
E
I
I
I
I
R
R
G
G
R
R
T
T
K
K
Q
Q
H
H
410
|
G
G
Q
Q
F
F
S
S
L
L
A
A
V
V
V
V
S
S
L
L
420
|
N
N
I
I
T
T
S
S
L
L
G
G
L
L
R
R
S
S
L
L
430
|
K
K
E
E
I
I
S
S
D
D
G
G
D
D
V
V
I
I
I
I
440
|
S
S
G
G
N
N
K
K
N
N
L
L
C
C
Y
Y
A
A
N
N
450
|
T
T
I
I
N
N
W
W
K
K
K
K
L
L
F
F
G
G
T
T
460
|
S
S
G
G
Q
Q
K
K
T
T
K
K
I
I
I
I
S
R
N
N
470
|
R
R
G
G
E
E
N
N
S
S
C
C
K
K
A
A
T
T
G
G
480
|
Q
Q
V
V
C
C
H
H
A
A
L
L
C
C
S
S
P
P
E
E
490
|
G
G
C
C
W
W
G
G
P
P
E
E
P
P
R
R
D
D
C
C
500
|
V
V
S
S
C
C
R
R
N
N
V
V
S
S
R
R
G
G
R
R
510
|
E
E
C
C
V
V
D
D
K
K
H
H
H
H
H
H
H
H
H
H
520
|
H
H
Click to Show/Hide the Structure
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) Click to Show/Hide
Key Molecule: GTPase KRas (KRAS) [4]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.31  Å
PDB: 6T5V
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6MNX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.14
TM score: 0.96411
Amino acid change:
Q61H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
C
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
S
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
H
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
L
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model DiFi cells Colon Homo sapiens (Human) CVCL_6895
DiFi-R cells Colon Homo sapiens (Human) CVCL_A2BW
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) [27]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease Info 
Molecule Alteration Missense mutation
p.G12C
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.60  Å
PDB: 8JGD
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.93157
Amino acid change:
G12C
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
C
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
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) [19]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease Info 
Molecule Alteration Structural variation
Copy number gain
 Molecule Info 
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) [19]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease Info 
Molecule Alteration Mutation
.
 Molecule Info 
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 PPARalpha-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma. Nat Commun. 2025 Feb 1;16(1):1237.
Ref 4 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 5 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 6 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 7 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 8 Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer. Integr Cancer Ther. 2021 Jan-Dec;20:15347354211045349.
Ref 9 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 10 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 11 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 12 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 13 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 14 TRAP1 enhances Warburg metabolism through modulation of PFK1 expression/activity and favors resistance to EGFR inhibitors in human colorectal carcinomas. Mol Oncol. 2020 Dec;14(12):3030-3047.
Ref 15 SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis. JCI Insight. 2023 Nov 8;8(21):e167874.
Ref 16 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 17 Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013 Aug;10(8):472-84. doi: 10.1038/nrclinonc.2013.110. Epub 2013 Jul 9.
Ref 18 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 19 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 20 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 21 HOXB8 mediates resistance to cetuximab in colorectal cancer cells through activation of the STAT3 pathway. Discov Oncol. 2024 Oct 29;15(1):603.
Ref 22 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 23 Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase. Nat Commun. 2023 May 30;14(1):3123.
Ref 24 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 25 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 26 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 27 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.

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