Genetic and ethnic modulation of cardiovascular toxicity of vascular endothelial growth factor inhibitors

Figures & data

Table 1. Vascular endothelial growth factor inhibitors.

Name	Mechanism	Route	Indication	Cardiovascular toxicity (reported)
Monoclonal Antibody
Bevacizumab	VEGF-A monoclonal antibody	IV	Colorectal cancer, non-squamous non-small cell lung cancer, glioblastoma, renal cell carcinoma, carcinoma of the cervix, epithelial ovarian, fallopian tube	Hypertension, heart failure, thromboembolic events, proteinuria, thrombotic microangiopathy, conduction disorder
Aflibercept	Monoclonal antibody to VEGF-A, VEGF-B, PGF	IV	Colorectal cancer	Hypertension, heart failure, thromboembolic events, proteinuria, thrombotic microangiopathy
Ramucirumab	VEGFR2 monoclonal antibody	IV	Colorectal cancer, non-small cell lung cancer, gastric cancer	Hypertension, thromboembolic events, proteinuria
Multi-Targeting Tyrosine Kinase Inhibitors with an Anti-VEGF Effect
Sunitinib	VEGFR1-3, PDGFRα/β, KIT, FLT3, CSF1R, RET	PO	Gastrointestinal stromal tumour, renal cell carcinoma, pancreatic neuroendocrine tumour	Hypertension, heart failure, myocardial ischemia/infarction, proteinuria, thrombotic microangiopathy, QTc prolongation, torsades de pointes
Sorafenib	VEGFR2, PDGFRβ, RAFs, KIT, FLT3, RET	PO	Hepatocellular carcinoma, renal cell carcinoma, differentiated thyroid carcinoma	Hypertension, heart failure, myocardial ischemia/infarction, proteinuria, QTc prolongation
Pazopanib	VEGFR1-3, PDGFRα/β, FGFR1/3, KIT, ITK, LCK, c-FMS	PO	Renal cell carcinoma, soft-tissue sarcoma	Hypertension, heart failure, myocardial ischemia/infarction, proteinuria, thrombotic microangiopathy, QTc prolongation, torsades de pointes
Axitinib	VEGFR1-3, PDGFRα/β, KIT	PO	Renal cell carcinoma	Hypertension, heart failure, thromboembolic events, proteinuria
Vandetanib	VEGFR1-3, EGFRs, RET, BRK, TIE2, EPHRs, Src kinases	PO	Medullary thyroid cancer	Hypertension, heart failure, myocardial ischemia/infarction, proteinuria, QTc prolongation, torsades de pointes
Regorafenib	VEGFR1-3, PDGFRα/β, FGFRs, RAFs, RET, KIT, TIE2, DDR2, TRKA, EPH2A, SAPK2, PTK5, Abl	PO	Gastrointestinal stromal tumour, colorectal cancer	Hypertension, myocardial ischemia/infarction, proteinuria
Cabozantinib	VEGFR1-3, MET, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT3, TIE2	PO	Renal cell carcinoma	Hypertension, thrombotic events, proteinuria
Lenvatinib	VEGFR1-3, PDGFRα, FGFRs, KIT, RET	PO	Differentiated thyroid cancer, renal cell carcinoma	Hypertension, heart failure, thromboembolic events, proteinuria, QTc prolongation
Under Investigation
Tivozanib	Tyrosine kinase inhibitor, under phase III trial for renal cell carcinoma
Lucitanib	Tyrosine kinase inhibitor, under phase II trial for breast cancer

VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; PGF: placental growth factor; PDGFR: platelet-derived growth factor receptor; FLT: feline McDonough sarcoma (FMS)-like tyrosine kinase; CSF1R: colony stimulating factor 1 receptor; RET: rearranged during transfection; RAF: rapidly accelerated fibrosarcoma; FGFR: fibroblast growth factor receptor; ITK: interleukin-2-inducible T-cell kinase; LCK: lymphocyte-specific protein tyrosine kinase; FMS: feline McDonough sarcoma; EGFR: epidermal growth factor receptor; BRK: breast tumour kinase; TIE: tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains; EPH: ephrins; Scr: sarcoma; DDR: discoidin domain receptor; TRK: tropomyosin receptor kinase; SAPK: stress-activated protein kinase; PTK: protein tyrosine kinase; ABL: Abelson murine leukaemia; MET: mesenchymal epithelial transition; AXL: anexelekto; ROS1: proto-oncogene tyrosine-protein kinase ROS; TYRO3: TYRO3 protein tyrosine kinase; MER: membrane oestrogen receptor; IV: intravenous; PO: oral (Reference: DailyMed; ClinicalTrials.gov).

Figure 1. Vascular endothelial growth factor (VEGF) and its associated signal pathways maintain vascular homeostasis through promoting endothelial cell proliferation, inducing two vasodilators, nitric oxide and prostacyclin, and reducing endothelin-1, a vasoconstrictor.

Figure 2. By blocking vascular endothelial growth factors (VEGFs), their receptors, or signal pathways, VEGF inhibitors undermine endothelial cell integrity and the balance between vasodilation and vasoconstriction, leading to hypertension, cardiac ischemia, thromboembolism, heart failure and microangiopathy.

Table 2. Potential effects of genetic polymorphism on hypertension induced by vascular endothelial growth factor inhibitors.

Cancer	Genetic Polymorphism/Markers	Toxic Effect
Bevacizumab
Breast cancer	VEGF-634 CC	Controversial results for hypertension [46,73]
	VEGF-1498 TT	Less hypertension [46]
	SV2C variant	More hypertension [71]
Colorectal cancer	VEGF-A c.*237C > T	More hypertension [72]
	VEGF-2578 C/C	Less hypertension [74]
	VEGF-936 C/C	Less hypertension [74]
Various solid cancers	EGLN3	More hypertension [75]
	EGF	More hypertension [75]
	KDR	Less hypertension [75]
	WNK1	More hypertension [75]
Sunitinib
Renal cell carcinoma	VEGF SNP-634 G/G	More hypertension [77]
	VEGF ACG haplotype-2578A > C	More hypertension [78]
	VEGF ACG haplotype-460C > T	More hypertension [78]
	VEGF ACG haplotype-405C > G	More hypertension [78]

Schneider BP, Wang M, Radovich M, et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. JCO. 2008;26:4672–4678.

 PubMed Web of Science ®Google Scholar

Etienne-Grimaldi MC, Formento P, Degeorges A, et al. Prospective analysis of the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-based therapy in metastatic breast cancer patients. Br J Clin Pharmacol. 2011;71:921–928.

 PubMed Web of Science ®Google Scholar

Schneider BP, Li L, Shen F, et al. Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100. Br J Cancer. 2014;111:1241–1248.

 PubMed Web of Science ®Google Scholar

Sibertin-Blanc C, Mancini J, Fabre A, et al. Vascular endothelial growth factor a c.*237C > T polymorphism is associated with bevacizumab efficacy and related hypertension in metastatic colorectal cancer. Digest Liver Dis. 2015;47:331–337.

 Web of Science ®Google Scholar

Morita S, Uehara K, Nakayama G, et al. Association between bevacizumab-related hypertension and vascular endothelial growth factor (VEGF) gene polymorphisms in Japanese patients with metastatic colorectal cancer. Cancer Chemother Pharmacol. 2013;71:405–411.

 PubMed Web of Science ®Google Scholar

Lambrechts D, Moisse M, Delmar P, et al. Genetic markers of bevacizumab-induced hypertension. Angiogenesis. 2014;17:685–694.

 PubMed Web of Science ®Google Scholar

Kim JJVS, Elson P, Rini BI, Ganapathi MK, Ganapathi R. VEGF single nucleotide polymorphisms (SNPs) and correlation to sunitinib-induced hypertension (HTN) in metastatic renal cell carcinoma (mRCC) patients (pts). J Clin Oncol. 2009;27(15S Suppl):5005.

 Web of Science ®Google Scholar

Eechoute K, van der Veldt AA, Oosting S, et al. Polymorphisms in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) predict sunitinib-induced hypertension. Clin Pharmacol Ther. 2012;92:503–510.

 PubMed Web of Science ®Google Scholar