VEGF Signaling and Targeted Therapies in Cancer: Molecular Mechanisms, Clinical Applications, Resistance, and Cardiorenal Toxicities
- 1Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72203, USA
- 2Arkansas Children’s Hospital, Little Rock, AR 72202, USA
Abstract
Vascular endothelial growth factor (VEGF) signaling is a central regulator of tumor angiogenesis and a major therapeutic target in oncology. VEGF-neutralizing agents and VEGF receptor tyrosine kinase inhibitors (VEGFR-TKIs) confer clinical benefit in multiple solid malignancies, but resistance and cardiovascular and renal toxicities can limit durable treatment. This review summarizes VEGF ligands, VEGF receptors, and the principal signaling mechanisms relevant to angiogenesis and lymphangiogenesis, with emphasis on VEGFR2 and VEGFR3 biology. We then examine established VEGF-targeted therapies, representative clinical evidence for VEGFR-TKIs, mechanisms of therapeutic resistance, and VEGF inhibitor-associated hypertension, endothelial dysfunction, proteinuria, and kidney injury. Particular attention is given to strategies for improving the therapeutic index of VEGF pathway inhibition, including risk assessment and toxicity monitoring, immunotherapy combinations, and emerging mechanism-based approaches. Modulation of the epoxyeicosatrienoic acid (EET)/soluble epoxide hydrolase axis is discussed as a promising experimental strategy for cardiorenal protection; however, current support is predominantly preclinical and requires clinical validation. Integrating tumor vascular biology with mechanisms of normal vascular and renal homeostasis may facilitate safer and more effective VEGF-directed cancer therapy.
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BibTeX
@article{mishra2026vegf,
title = {{VEGF Signaling and Targeted Therapies in Cancer: Molecular Mechanisms, Clinical Applications, Resistance, and Cardiorenal Toxicities}},
author = {Abhishek Mishra and Md. Abdul Hye Khan and Ripa Jamal and Ilham Kadhim and John D. Imig},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209376},
url = {https://www.mdpi.com/1422-0067/27/20/9376},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - VEGF Signaling and Targeted Therapies in Cancer: Molecular Mechanisms, Clinical Applications, Resistance, and Cardiorenal Toxicities
AU - Abhishek Mishra
AU - Md. Abdul Hye Khan
AU - Ripa Jamal
AU - Ilham Kadhim
AU - John D. Imig
PY - 2026
DA - 2026/10/21
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209376
UR - https://www.mdpi.com/1422-0067/27/20/9376
AB - Vascular endothelial growth factor (VEGF) signaling is a central regulator of tumor angiogenesis and a major therapeutic target in oncology. VEGF-neutralizing agents and VEGF receptor tyrosine kinase inhibitors (VEGFR-TKIs) confer clinical benefit in multiple solid malignancies, but resistance and cardiovascular and renal toxicities can limit durable treatment. This review summarizes VEGF ligands, VEGF receptors, and the principal signaling mechanisms relevant to angiogenesis and lymphangiogenesis, with emphasis on VEGFR2 and VEGFR3 biology. We then examine established VEGF-targeted therapies, representative clinical evidence for VEGFR-TKIs, mechanisms of therapeutic resistance, and VEGF inhibitor-associated hypertension, endothelial dysfunction, proteinuria, and kidney injury. Particular attention is given to strategies for improving the therapeutic index of VEGF pathway inhibition, including risk assessment and toxicity monitoring, immunotherapy combinations, and emerging mechanism-based approaches. Modulation of the epoxyeicosatrienoic acid (EET)/soluble epoxide hydrolase axis is discussed as a promising experimental strategy for cardiorenal protection; however, current support is predominantly preclinical and requires clinical validation. Integrating tumor vascular biology with mechanisms of normal vascular and renal homeostasis may facilitate safer and more effective VEGF-directed cancer therapy.
SN - 1422-0067
ER -