logo
    Docs
 

Target: KDR


Research on KDR (Kinase Insert Domain Receptor)

1. Target Summary:

KDR, also known as VEGFR-2 (Vascular Endothelial Growth Factor Receptor 2), is a receptor tyrosine kinase that plays a critical role in angiogenesis, the process of new blood vessel formation. It is primarily activated by vascular endothelial growth factor (VEGF), which is crucial for endothelial cell proliferation, migration, and survival. KDR is implicated in various cancers, where its expression and mutations can influence tumor growth, metastasis, and response to therapies.

2. Mechanism:

KDR is activated upon binding with VEGF, leading to receptor dimerization and autophosphorylation. This activation triggers several downstream signaling pathways, including:
  • PI3K/Akt Pathway: Promotes cell survival and growth.
  • MAPK/ERK Pathway: Involved in cell proliferation and differentiation.
  • PLCĪ³ Pathway: Leads to increased intracellular calcium levels and further cellular responses.
The activation of these pathways results in enhanced endothelial cell proliferation, migration, and the formation of new blood vessels, which are essential for tumor growth and metastasis (Ferrara N, 2024; Wang F, Liu G, 2022).

3. Approved Drugs:

Several drugs target KDR, primarily focusing on its role in angiogenesis:
  • Bevacizumab (Avastin): A monoclonal antibody that inhibits VEGF, thereby preventing its interaction with KDR.
  • Cabozantinib (Cabometyx): A multitargeted tyrosine kinase inhibitor that inhibits KDR among other receptors.
  • Apatinib: A selective inhibitor of KDR that has shown efficacy in various cancers.

4. Hypotheses:

  • KDR Mutations and Treatment Resistance: Variants in the KDR gene may lead to altered receptor activity, affecting the efficacy of anti-VEGF therapies like bevacizumab. For instance, the 889 C>T mutation in KDR has been associated with poorer progression-free survival (PFS) and overall survival (OS) in colorectal cancer patients treated with bevacizumab (Wang F, Liu G, 2022).
  • KDR Expression as a Prognostic Marker: High expression levels of KDR may correlate with aggressive tumor behavior and poor prognosis in various cancers, including breast cancer and colorectal cancer (Mehmood A et al., 2025).

5. Validation:

KDR has been validated as a significant target in cancer therapy through various studies:
  • Genetic Studies: Amplifications of KDR have been associated with poor prognosis in cancers such as glioblastoma and anaplastic thyroid cancer (Pozdeyev N et al., 2018; Carlotto BS et al., 2023).
  • Clinical Outcomes: Studies have shown that specific KDR mutations correlate with treatment outcomes, such as the 889 C>T mutation affecting the effectiveness of bevacizumab in colorectal cancer (Wang F, Liu G, 2022).

6. Clinical Trials:

Numerous clinical trials are ongoing to evaluate the efficacy of KDR-targeted therapies:
  • Trials assessing the effectiveness of cabozantinib in various cancers, including medullary thyroid cancer, have shown promising results (Krajewska J et al., 2016).
  • Studies investigating the role of KDR polymorphisms in predicting treatment responses in colorectal cancer and other malignancies.

7. Involved Pathways:

KDR is primarily involved in the VEGF signaling pathway, which regulates angiogenesis. Other pathways include:
  • PI3K/Akt Pathway: Promotes cell survival and growth.
  • MAPK/ERK Pathway: Involved in cell proliferation and differentiation.

8. Associated Genes:

KDR is often studied alongside other genes involved in angiogenesis and cancer progression, including:
  • VEGF: The primary ligand for KDR.
  • FLT1 (VEGFR-1): Another receptor for VEGF that can modulate KDR signaling.
  • PDGFRA: Often co-amplified with KDR in various cancers (Disel U et al., 2020).

9. Target Expression:

KDR is expressed in endothelial cells and various tumor types. Its expression levels can vary significantly based on tumor type and stage, influencing angiogenesis and tumor growth.

10. Additional Context:

KDR's role in cancer is multifaceted, as it not only promotes angiogenesis but also influences tumor microenvironment interactions. Its mutations and expression levels can serve as biomarkers for prognosis and treatment response, making it a critical target for therapeutic intervention.

11. References:

  • Ferrara N. (2024). "Molecular Basis of Angiogenesis." The Keio Journal of Medicine.
  • Wang F, Liu G. (2022). "Influence of KDR Genetic Variation on the Effectiveness and Safety of Bevacizumab in the First-Line Treatment for Patients with Advanced Colorectal Cancer." International Journal of General Medicine. PMID: 35734201.
  • Mehmood A, Li R, Kaushik AC. (2025). "Comparative analysis of the genomic and expression profiles of ANLN and KDR as prognostic markers in breast cancer." In Silico Pharmacology. PMID: 39831055.
  • Pozdeyev N, Gay LM, Sokol ES. (2018). "Genetic Analysis of 779 Advanced Differentiated and Anaplastic Thyroid Cancers." Clinical Cancer Research. PMID: 29615459.
  • Disel U, Madison R, Abhishek K. (2020). "The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA." The Oncologist. PMID: 31604903.
  • Krajewska J, Olczyk T, Jarzab B. (2016). "Cabozantinib for the treatment of progressive metastatic medullary thyroid cancer." Expert Review of Clinical Pharmacology. PMID: 26536165.
  • Carlotto BS, Trevisan P, Provenzi VO. (2023). "PDGFRA, KIT, and KDR Gene Amplification in Glioblastoma: Heterogeneity and Clinical Significance." Neuromolecular Medicine. PMID: 37610648.