Drug Information

Drug (ID: DG00341) and It's Reported Resistant Information
Name
Panitumumab
Synonyms
Vectibix; Panitumumab (genetical recombination); Vectibix (TN); Panitumumab (USAN/INN); Panitumumab (genetical recombination) (JAN); Panitumumab (EGFR mAb inhibitor)
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Indication
In total 2 Indication(s)
Colorectal cancer [ICD-11: 2B91]
Approved
[1]
Head and neck cancer [ICD-11: 2D42]
Phase 2
[1]
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Colorectal cancer [ICD-11: 2B91]
[2]
Metastatic colorectal cancer [ICD-11: 2D85]
[3]
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
D0HU9H
DrugBank ID
DB01269
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
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) [1]
Molecule Alteration Missense mutation
p.G465E
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]
Molecule Alteration Missense mutation
p.V600E
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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.
Key Molecule: GTPase KRas (KRAS) [4]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
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 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) [1]
Molecule Alteration Structural variation
Amplification
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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) [1]
Molecule Alteration Structural variation
Amplification
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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 Nras (NRAS) [1]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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) [1]
Molecule Alteration Missense mutation
p.G12V
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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) [1]
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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) [1]
Molecule Alteration Structural variation
Amplification
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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) [1]
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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) [5]
Molecule Alteration Structural variation
Copy number gain
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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: GTPase KRas (KRAS) [2], [6]
Molecule Alteration Missense mutation
p.G12V
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: GTPase KRas (KRAS) [2]
Molecule Alteration Missense mutation
p.G12R
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: GTPase KRas (KRAS) [2]
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: GTPase KRas (KRAS) [2]
Molecule Alteration Missense mutation
p.G12A
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: GTPase KRas (KRAS) [2]
Molecule Alteration Missense mutation
p.G12S
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: GTPase KRas (KRAS) [2]
Molecule Alteration Missense mutation
p.G12C
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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		 Ligation assay; BEAMing assay
Experiment for
Drug Resistance		 Progression-free survival analysis; Overall survival analysis
Mechanism Description Our study indicates that the resistance mutations in kRAS and other genes were highly likely to be present in a clo.l subpopulation within the tumors prior to the initiation of panitumumab therapy.
Key Molecule: Hepatocyte growth factor receptor (MET) [3]
Molecule Alteration Structural variation
Amplification
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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 Nras (NRAS) [3]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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.
Metastatic colorectal cancer [ICD-11: 2D85]
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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) [6]
Molecule Alteration Missense mutation
p.S492R
 Molecule Info 
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease 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) [4]
Molecule Alteration Missense mutation
p.G12C
 Molecule Info 
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease 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) [3]
Molecule Alteration Mutation
.
 Molecule Info 
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease 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) [3]
Molecule Alteration Structural variation
Copy number gain
 Molecule Info 
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease 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) [7]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Metastatic colorectal cancer [ICD-11: 2D85.0]
 Disease 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 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 2 The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012 Jun 28;486(7404):537-40. doi: 10.1038/nature11219.
Ref 3 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 4 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 5 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 6 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 7 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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