Endothelium as a Source of Cardiovascular Toxicity From Antitumor Kinase Inhibitors

Abstract

Kinase inhibitors (KIs) targeting oncogenic molecular pathways have revolutionized cancer therapy. By directly targeting specific tumor-driving kinases, targeted therapies have fewer side effects compared with chemotherapy. Despite the enhanced specificity, cardiovascular side effects have emerged with many targeted cancer therapies that limit long-term outcomes in patients with cancer. Endothelial cells lining all blood vessels are critical to cardiovascular health and are also exposed to circulating levels of systemic anticancer therapies. Both on- and off-target perturbation of signaling pathways from KIs can cause endothelial dysfunction, resulting in cardiovascular toxicity. As such, the endothelium is a potential source, and also a therapeutic target for prevention, of cardiovascular toxicity. In this review, we examine the evidence for KI-induced endothelial cell dysfunction as a mechanism for the cardiovascular toxicities of vascular endothelial growth factor inhibitors, BCR-Abl (breakpoint cluster region-Abelson proto-oncogene) KIs, Bruton tyrosine inhibitors, and emerging information regarding endothelial toxicity of newer classes of KIs.

Keywords: cardio-oncology; cardiotoxicity; endothelium; receptors, vascular endothelial growth factor; tyrosine kinase inhibitors.

Figure 1.. Evolving Understanding of Endothelial Toxicity as a Mechanism for Cardiovascular Side Effects of Anti-Cancer Kinase Inhibitor Therapies.

A Some of the BCR-Abl tyrosine kinase inhibitors (TKI) cause arterial thrombosis and these agents also increase endothelial cell (EC) surface adhesion molecule expression, impair EC viability, and increase RhoA kinase activity. Only dasatinib disrupts actin organization to induce EC permeability, consistent with the side effect of pleural effusions. B. VEGFRIs decrease eNOS phosphorylation leading to impaired vascular relaxation and increase ET levels and microparticle release promoting vasoconstriction resulting in hypertension and heart failure. VEGFRIs also disrupt glomerular EC and podocyte function resulting in renal dysfunction which further contributes to hypertension. C. BTKIs decrease B-cell lymphoma 2A1 and increase bone morphogenic protein 4 expression in vascular ECs leading to apoptosis and decreased angiogenesis. Whether this EC toxicity contributes to the development of atrial fibrillation or hypertension with these agents is unknown. Created in Biorender.