Vascular Impact of Cancer Therapies: The Case of BTK (Bruton Tyrosine Kinase) Inhibitors

Abstract

Novel targeted cancer therapies have revolutionized oncology therapies, but these treatments can have cardiovascular complications, which include heterogeneous cardiac, metabolic, and vascular sequelae. Vascular side effects have emerged as important considerations in both cancer patients undergoing active treatment and cancer survivors. Here, we provide an overview of vascular effects of cancer therapies, focusing on small-molecule kinase inhibitors and specifically inhibitors of BTK (Bruton tyrosine kinase), which have revolutionized treatment and prognosis for B-cell malignancies. Cardiovascular side effects of BTK inhibitors include atrial fibrillation, increased risk of bleeding, and hypertension, with the former 2 especially providing a treatment challenge for the clinician. Cardiovascular complications of small-molecule kinase inhibitors can occur through either on-target (targeting intended target kinase) or off-target kinase inhibition. We will review these concepts and focus on the case of BTK inhibitors, highlight the emerging data suggesting an off-target effect that may provide insights into development of arrhythmias, specifically atrial fibrillation. We believe that cardiac and vascular sequelae of novel targeted cancer therapies can provide insights into human cardiovascular biology.

Keywords: atrial fibrillation; cancer survivors; hypertension; prognosis; protein-tyrosine kinases.

Figure 1:

Targeting kinases and VEGFR in the treatment of cancer. Panel A: Kinase inhibition can be achieved through targeting the kinase receptor ligand or kinase receptor, usually through binding of a monoclonal antibody (mAb) that is given as an intravenous infusion. Small-molecule kinase inhibitors, taken orally, work intracellularly and may bind more than one kinase. Panel B: VEGF-targeted therapies include a monoclonal antibody and ligand trap against circulating VEGFA, a monoclonal antibody against VEGF receptor 2 (VEGFR2), and multitargeted tyrosine kinase inhibitors with anti-VEGF activity.

Figure 2:

B-cell receptor and downstream tyrosine-kinase signaling in B-cell tumor growth. BCAP: B-cell PI3K adaptor protein; BCR: B-cell receptor; BTK: Bruton’s tyrosine kinase; ITAM: immunoreceptor tyrosine-based activation motif; PI3K: PI3 kinase; SYK: tyrosine protein kinase Syk; PIP2: phosphatidylinositol 4,5-biphosphate; PIP3: phosphatidylinositol-3,4,5-triphoshate.

Figure 3:

BTK inhibitor blockage of platelet activation and aggregation. GPVI: collagen receptor Glycoprotein VI; GP1b: platelet membrane glycoprotein 1b; Platelet specific integrin alpha IIb/beta 3, αIIbβ3 integrin; VWF: Von Willebrand Factor.