Disease Information

General Information of the Disease (ID: DIS00105)
Name
Metastatic colorectal cancer
ICD
ICD-11: 2D85
Resistance Map
Type(s) of Resistant Mechanism of This Disease
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
3 drug(s) in total
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Cetuximab
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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) [1]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Molecule Alteration Missense mutation
p.S492R
 Molecule Info 
Resistant Drug Cetuximab
 Drug Info 
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) [2]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Resistant Drug Cetuximab
 Drug Info 
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) [3]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Molecule Alteration Missense mutation
p.G12C
 Molecule Info 
Resistant Drug Cetuximab
 Drug Info 
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) [4]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Molecule Alteration Structural variation
Copy number gain
 Molecule Info 
Resistant Drug Cetuximab
 Drug 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) [4]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Drug Cetuximab
 Drug 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.
Fluorouracil
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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: Mediator of RNA polymerase II transcription subunit 12 (MED12) [5]
Resistant Disease Middle eastern colorectal cancer [ICD-11: 2D85.1]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Drug Fluorouracil
 Drug Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
TGF-beta signaling pathway Inhibition hsa04350
In Vitro Model DLD1 cells Colon Homo sapiens (Human) CVCL_0248
LOVO cells Colon Homo sapiens (Human) CVCL_0399
Experiment for
Molecule Alteration		 Whole genome sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Clinical manifestations assay
Mechanism Description However, it is worth noting that 50% of MED12-mutated patients with CRC who underwent chemotherapy (4/8) showed poor response to standard chemotherapy.
Key Molecule: Mediator of RNA polymerase II transcription subunit 12 (MED12) [5]
Resistant Disease Middle eastern colorectal cancer [ICD-11: 2D85.1]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Drug Fluorouracil
 Drug Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
TGF-beta signaling pathway Inhibition hsa04350
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
DLD1 cells Colon Homo sapiens (Human) CVCL_0248
CaCo2 cells Colon Homo sapiens (Human) CVCL_0025
HCT116 cells Colon Homo sapiens (Human) CVCL_0291
LOVO cells Colon Homo sapiens (Human) CVCL_0399
HCT15 cells Colon Homo sapiens (Human) CVCL_0292
CL34 cells Colon Homo sapiens (Human) CVCL_1980
Colo-320 cells Colon Homo sapiens (Human) CVCL_1989
Experiment for
Molecule Alteration		 Immunoblotted assay; Fluorescence immunostaining assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description We also show that MED12 deficiency confers resistance to chemotherapy at the tissue culture level. MED12 is a likely tumour suppressor that modulates TGF-beta-induced epithelial-mesenchymal transition signalling in CRC cell lines.
Key Molecule: Mediator of RNA polymerase II transcription subunit 12 (MED12) [5]
Resistant Disease Middle eastern colorectal cancer [ICD-11: 2D85.1]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Drug Fluorouracil
 Drug Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
TGF-beta signaling pathway Inhibition hsa04350
Experiment for
Molecule Alteration		 Whole genome sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Clinical manifestations assay
Mechanism Description However, it is worth noting that 50% of MED12-mutated patients with CRC who underwent chemotherapy (4/8) showed poor response to standard chemotherapy.
Panitumumab
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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) [1]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Molecule Alteration Missense mutation
p.S492R
 Molecule Info 
Resistant Drug Panitumumab
 Drug Info 
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 Nras (NRAS) [3]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Molecule Alteration Missense mutation
p.G12C
 Molecule Info 
Resistant Drug Panitumumab
 Drug Info 
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: Serine/threonine-protein kinase B-raf (BRAF) [4]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Drug Panitumumab
 Drug Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation RAS/MEk/ERK signaling pathway Inhibition hsa04010
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: Hepatocyte growth factor receptor (MET) [4]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Molecule Alteration Structural variation
Copy number gain
 Molecule Info 
Resistant Drug Panitumumab
 Drug 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: Epidermal growth factor receptor (EGFR) [6]
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Drug Panitumumab
 Drug Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
EGFR signaling pathway Activation hsa01521
ERBB2/MET/IGF-1R signalling pathway Activation hsa04520
RAF/KRAS/MEK signaling pathway Activation hsa04010
PI3K/AKT/mTOR signaling pathway Activation hsa04151
Experiment for
Drug Resistance		 Progression-free survival (PFS) analysis; Overall survival (OS) analysis
Mechanism Description Cetuximab and panitumumab are monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) that are effective agents for metastatic colorectal cancer (mCRC). The mechanisms of resistance refer to intrinsic and extrinsic alterations of tumours. The intrinsic mechanisms include EGFR ligand overexpression, EGFR alteration, RAS/RAF/PI3K gene mutations, ERBB2/MET/IGF-1R activation, metabolic remodelling, microsatellite instability and autophagy. Extrinsic alterations mainly disrupt the tumour microenvironment, specifically immune cells, cancer-associated fibroblasts (CAFs) and angiogenesis.
References
Ref 1 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 2 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 3 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.
Ref 4 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 5 MED12 is recurrently mutated in Middle Eastern colorectal cancer. Gut. 2018 Apr;67(4):663-671. doi: 10.1136/gutjnl-2016-313334. Epub 2017 Feb 9.
Ref 6 Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies .J Exp Clin Cancer Res. 2021 Oct 18;40(1):328. doi: 10.1186/s13046-021-02130-2. 10.1186/s13046-021-02130-2

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