The Vascular Endothelial Growth Factor Receptor (VEGFR) and Cancer

Year 2025, Volume: 4 Issue: 2, 91 - 103, 03.09.2025

Okan Aykaç , İrem Bozbey Merde

https://doi.org/10.71133/anatphar.1652647

Abstract

Cancer continues to maintain its importance as a pathological event whose incidence continues to increase. Since the source of pathophysiology is multifaceted, it is one of the popular topics that pharmaceutical and medicinal chemists attach importance to in their studies. In recent studies, when the concept of cancer is considered, it has been observed that it is associated with the mechanism of vascular formation and the mechanisms of action of drugs. Thus, the mechanism of angiogenesis and EGF and VGF systemic pathways that play a great factor in angiogenesis have been elucidated. Inhibition of these systems was targeted while designing drugs and VEGFR (Vascular Endothelial Growth Receptors) emerged. The aim of this study is to compile the types of VEGFR, their relationship with cancer and the mechanisms of action of clinically used drugs approved by various authorities and to enable the readers of this review to recognize the specificities in targets in VEGFR inhibitor design.

Keywords

Angiogenesis , Cancer , Tyrosine kinase inhibitors , VEGFR

References

• Dekuang Zhao et al. VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2. Oncogene, 2014; 3107-3119. https://doi.org/10.1038/onc.2014.257
• Ferrara, N. Vascular endothelial growth factor: Basic science and clinical progress. Endocrinology Reviews, 2004.
• Li, W., Wei, J., Cheng, M., & Liu, M. Unveiling promising targets in gastric cancer therapy: A comprehensive review. Molecular Therapy: Oncology, 2004; 32(32), 200857.
• Chen, Y., et al. Immunotherapy-based combination strategies for treatment of EGFR-TKI-resistant non-small-cell lung cancer. Future Medicine Ltd, 2024.
• Yang, Z., et al. Opportunities and Challenges of Nanoparticles in Digestive Tumors as Anti-Angiogenic Therapies. Frontiers in Oncology, 2024.
• Hegde, P. S., & Chen, D. S. Top 10 Challenges in Cancer Immunotherapy. Immunity, 2024.
• Li, B., Jin, J., Guo, D., Tao, Z., & Hu, X. Immune Checkpoint Inhibitors Combined with Targeted Therapy: The Recent Advances and Future Potentials. Cancers, 2023; 15(15), 2858.
• Song, Z., Tao, Y., Liu, Y., & Li, J. Advances in delivery systems for CRISPR/Cas-mediated cancer treatment: a focus on viral vectors and extracellular vesicles. Frontiers in Immunology, 2024.
• Zhou, Y., et al. The Role of the VEGF Family in Coronary Heart Disease. Frontiers in Cardiovascular Medicine, 2021.
• Shah, A. A., Kamal, M. A., & Akhtar, S. Tumor Angiogenesis and VEGFR-2: Mechanism, Pathways and Current Biological Therapeutic Interventions. Current Drug Metabolism, 2022; 22(22), 50–59.
• Craige, S., Kaur, G., Bond, J., Caliz, A., Kant, S., & Keaney, J. Endothelial Reactive Oxygen Species: Key Players in Cardiovascular Health and Disease. Antioxidants & Redox Signaling.Rosen, L. S. VEGF-Targeted Therapy: Therapeutic Potential and Recent Advances. The Oncologist, 2005; 10, 382–391.
• Ferrara, N., Gerber, H. P., & LeCouter, J. The biology of VEGF and its receptors. Nature Medicine, 2003.
• Brown, G. C., Brown, M. M., Rapuano, S. B., & Boyer, D. A Cost-Benefit Analysis of VEGF-Inhibitor Therapy for Neovascular Age-Related Macular Degeneration in the United States. American Journal of Ophthalmology, 2021; 223(223), 405–429.
• Zhou, Y., et al. The Role of VEGF Family in Lipid Metabolism. Current Pharmaceutical Biotechnology, 2022; 24(24), 253–265.
• Qi, L., et al. VEGFR-3 signaling restrains the neuron-macrophage crosstalk during neurotropic viral infection. Cell Reports, 2023; 42(42).
• Huang, Z., et al. Hypoxia makes EZH2 inhibitor not easy—advances of crosstalk between HIF and EZH2. Life Metabolism, 2024; 3(3).
• Chen, L., et al. How to overcome tumor resistance to anti-PD-1/PD-L1 therapy by immunotherapy modifying the tumor microenvironment in MSS CRC. Clinical Immunology, 2024.
• Hu, L., Zhang, N., Zhao, C., & Pan, J. Engineering ADSCs by manipulating YAP for lymphedema treatment in a mouse tail model. Experimental Biology and Medicine, 2024; 249(249), 10295.
• VEGF signaling pathway - Reference pathway. Retrieved from https://www.kegg.jp/pathway/map04370.
• Muller, Y. A., Christinger, H. W., Keyt, B. A., & De Vos, A. M. The crystal structure of vascular endothelial growth factor (VEGF) refined to 1.93 Å resolution: Multiple copy flexibility and receptor binding. Structure, 1997; 5(5), 1325–1338.
• Cao, J., Chow, L., & Dow, S. Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment. Frontiers in Oncology, 2023.
• Abdelnaby, R. M., et al. In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers. Pharmaceuticals, 2022; 15(15).
• Tian, Y., et al. Effect of Electric Fields on the Mechanical Mechanism of Regorafenib–VEGFR2 Interaction to Enhance Inhibition of Hepatocellular Carcinoma. Biomolecules, 2025; 15(15).
• Iyer, R., Fetterly, G., Lugade, A., & Thanavala, Y. Sorafenib: A clinical and pharmacologic review. Expert Opinion on Pharmacotherapy, 2010.
• Keating, G. M. Sorafenib: A Review in Hepatocellular Carcinoma. Drugs, 2017; 77(77), 583–593.
• Keating, G. M., & Santoro, A. Sorafenib: A review of its use in advanced hepatocellular carcinoma. Drugs, 2009; 69(69), 2057–2077.
• Abd Elhameed, A. A., Ali, A. R., Ghabbour, H. A., Bayomi, S. M., & El-Gohary, N. S. Probing structural requirements for thiazole-based mimetics of sunitinib as potent VEGFR-2 inhibitors. RSC Medicinal Chemistry, 2025.
• Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. Retrieved from https://go.drugbank.com/articles/A2291.
• Podar, K., et al. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proceedings of the National Academy of Sciences, 2006; 103(103), 19478–19483.
• Annuryanti, F., et al. Development of axitinib-loaded polymeric ocular implants for the treatment of posterior ocular diseases. International Journal of Pharmaceutics, 2025 ;669(669).
• Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. Retrieved from https://go.drugbank.com/articles/A6910.
• Arena, Claudia, et al. Stomatitis and VEGFR‐Tyrosine Kinase Inhibitors (VR‐TKIs): A Review of Current Literature in 4369 Patients. BioMed Research International, 2018; 5035217.
• Luo, D., Liu, Y., Lu, Z., & Huang, L. Targeted therapy and immunotherapy for gastric cancer: rational strategies, novel advancements, challenges, and future perspectives. Molecular Medicine, 2025; 31(31), 52.
• Casak, S. J., et al. FDA approval summary: Ramucirumab for gastric cancer. Clinical Cancer Research, 2015; 21(21), 3372–3376.
• Yang, Haoran, et al. Emerging Gene Therapy Based on Nanocarriers: A Promising Therapeutic Alternative for Cardiovascular Diseases and a Novel Strategy in Valvular Heart Disease. International Journal of Molecular Sciences 2025; 4(4), 1743.
• Ahmad, Ajmal, and Mohd Imtiaz Nawaz. Molecular mechanism of VEGF and its role in pathological angiogenesis. Journal of cellular biochemistry, 2022; 11(11), 1938-1965.
• Saeed, Anwaar, et al. S2303: phase II/III trial of paclitaxel+ ramucirumab±nivolumab in gastric and esophageal adenocarcinoma (PARAMUNE). Future Oncology, 2025; 1-7.
• Choi, Dong Kyu. Epigenetic regulation of angiogenesis and its therapeutics. Genomics & Informatics, 2025; 1-11.