Molecule Information

General Information of the Molecule (ID: Mol01832)

• Name: VEGF-2 receptor (KDR) ,Homo sapiens
• Synonyms: VEGFR-2; Fetal liver kinase 1; FLK-1; Kinase insert domain receptor; KDR; Protein-tyrosine kinase receptor flk-1; CD antigen CD309; KDR; FLK1; VEGFR2
• Molecule Type: Protein
• Gene Name: KDR
• Gene ID: 3791
• Location: chr4:55,078,48155,125,595 [-]
• Sequence:
  MQSKVLLAVALWLCVETRAASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLD
  WLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQD
  YRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWD
  SKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGE
  KLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRS
  DQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPP
  EIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVP
  PQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAVSVTNPY
  PCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGE
  RVISFHVTRGPEITLQPDMQPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPT
  PVCKNLDTLWKLNATMFSNSTNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLT
  VLERVAPTITGNLENQTTSIGESIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNR
  NLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLEIIILVGTAVIAMFFWL
  LLVIILRTVKRANGGELKTGYLSIVMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPL
  GRGAFGQVIEADAFGIDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVN
  LLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRNEFVPYKTKGARFRQGKDYVGAIPVDLK
  RRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFLTLEHLICYSFQVAKGMEFLA
  SRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDR
  VYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTML
  DCWHGEPSQRPTFSELVEHLGNLLQANAQQDGKDYIVLPISETLSMEEDSGLSLPTSPVS
  CMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFEDIPLEEPEVKVIPDDNQTDS
  GMVLASEELKTLEDRTKLSPSFGGMVPSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYS
  SEEAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPV
• 3D-structure: PDB ID: 3V2A; Classification: Hormone/signaling protein; Method: X-ray diffraction; Resolution: 3.20 Å
• Function: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.
• Uniprot ID: VGFR2_HUMAN
• Ensembl ID: ENSG00000128052
• HGNC ID: HGNC:6307

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Cabozantinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [1]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Cabozantinib
• Molecule Alteration: Missense mutation; p.R1032Q (c.3095G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: VEGF signaling pathway; Activation; hsa04370
• In Vitro Model: Colo-320 cells; Colon; Homo sapiens (Human); CVCL_1989
• In Vitro Model: MDST8 cells; Colon; Homo sapiens (Human); CVCL_2588
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: BEAMing assay; Western blot analysis; immunofluorescence assay
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs.

Lenvatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [1]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Lenvatinib
• Molecule Alteration: Missense mutation; p.R1032Q (c.3095G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: VEGF signaling pathway; Activation; hsa04370
• In Vitro Model: Colo-320 cells; Colon; Homo sapiens (Human); CVCL_1989
• In Vitro Model: MDST8 cells; Colon; Homo sapiens (Human); CVCL_2588
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: BEAMing assay; Western blot analysis; immunofluorescence assay
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs.

Regorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [1]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Regorafenib
• Molecule Alteration: Missense mutation; p.L840F (c.2518C>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: VEGF signaling pathway; Inhibition; hsa04370
• In Vitro Model: Colo-320 cells; Colon; Homo sapiens (Human); CVCL_1989
• In Vitro Model: MDST8 cells; Colon; Homo sapiens (Human); CVCL_2588
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: BEAMing assay; Western blot analysis; immunofluorescence assay
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [2]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Regorafenib
• Molecule Alteration: Missense mutation; p.R961W (c.2881C>T)
• Experimental Note: Identified from the Human Clinical Data

Sunitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Clear cell renal cell carcinoma [ICD-11: 2C90.Y] [3]

• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Resistant Drug: Sunitinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1alpha/VEGFA/VEGFR signalling pathway; Regulation; N.A.
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1.

Clinical Trial Drug(s) 1 drug(s) in total

AUY922

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Clear cell renal cell carcinoma [ICD-11: 2C90.Y] [3]

• Sensitive Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Sensitive Drug: AUY922
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1alpha/VEGFA/VEGFR signalling pathway; Regulation; N.A.
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1.

Preclinical Drug(s) 1 drug(s) in total

Unspecified VEGFR2 antibody

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Melanoma [ICD-11: 2C30.0] [4]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Unspecified VEGFR2 antibody
• Molecule Alteration: Missense mutation; p.Q472H (c.1416A>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: WM3248 cells; Skin; Homo sapiens (Human); CVCL_6798
• In Vitro Model: WM1575 cells; Skin; Homo sapiens (Human); CVCL_L027
• Experiment for Molecule Alteration: Targeted NGS assay
• Experiment for Drug Resistance: Proliferation assay; Invasion assay

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Melanoma [ICD-11: 2C30]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Skin
• The Specified Disease: Melanoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.84E-01; Fold-change: 1.99E-01; Z-score: 1.49E-01

References

• Ref 1: Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic TherapiesClin Cancer Res. 2018 Aug 1;24(15):3550-3559. doi: 10.1158/1078-0432.CCR-18-0103. Epub 2018 Mar 27.
• Ref 2: KDR Mutation as a Novel Predictive Biomarker of Exceptional Response to Regorafenib in Metastatic Colorectal CancerCureus. 2016 Feb 3;8(2):e478. doi: 10.7759/cureus.478.
• Ref 3: AUY922 improves sensitivity to sunitinib in clear cell renal cell carcinoma based on network pharmacology and in vitro experiments. Heliyon. 2024 Jul 18;10(14):e34834.
• Ref 4: Identification of a Novel Pathogenic Germline KDR Variant in MelanomaClin Cancer Res. 2016 May 15;22(10):2377-85. doi: 10.1158/1078-0432.CCR-15-1811. Epub 2015 Dec 2.