Multiparameter Evaluation of the Platelet-Inhibitory Effects of Tyrosine Kinase Inhibitors Used for Cancer Treatment.

Bibian Tullemans,Johannes Eble,Paola Van Der Meijden,Maureen Aarts,Alicia Veninga,Johan Heemskerk,Delia Fernandez,Marijke Kuijpers

doi:10.3390/ijms222011199

Abstract

Current antiplatelet drugs for the treatment of arterial thrombosis often coincide with increased bleeding risk. Several tyrosine kinase inhibitors (TKIs) for cancer treatment inhibit platelet function, with minor reported bleeding symptoms. The aim of this study was to compare the antiplatelet properties of eight TKIs to explore their possible repurposing as antiplatelet drugs. Samples of whole blood, platelet-rich plasma (PRP), or isolated platelets from healthy donors were treated with TKI or the vehicle. Measurements of platelet aggregation, activation, intracellular calcium mobilization, and whole-blood thrombus formation under flow were performed. Dasatinib and sunitinib dose-dependently reduced collagen-induced aggregation in PRP and washed platelets; pazopanib, cabozantinib, and vatalanib inhibited this response in washed platelets only; and fostamatinib, axitinib, and lapatinib showed no/limited effects. Fostamatinib reduced thrombus formation by approximately 50% on collagen and other substrates. Pazopanib, sunitinib, dasatinib, axitinib, and vatalanib mildly reduced thrombus formation on collagen by 10–50%. Intracellular calcium responses in isolated platelets were inhibited by dasatinib (>90%), fostamatinib (57%), sunitinib (77%), and pazopanib (82%). Upon glycoprotein-VI receptor stimulation, fostamatinib, cabozantinib, and vatalanib decreased highly activated platelet populations by approximately 15%, while increasing resting populations by 39%. In conclusion, the TKIs with the highest affinities for platelet-expressed molecular targets most strongly inhibited platelet functions. Dasatinib, fostamatinib, sunitinib, and pazopanib interfered in early collagen receptor-induced molecular-signaling compared with cabozantinib and vatalanib. Fostamatinib, sunitinib, pazopanib, and vatalanib may be promising for future evaluation as antiplatelet drugs.

Highlights

Ischemic heart disease and stroke accounted for >15 million deaths worldwide in2019, making arterial thrombosis a leading global cause of death [1]
In this work, we explored the antiplatelet properties of the tyrosine kinase inhibitors (TKIs) dasatinib, fostamatinib, sunitinib, pazopanib, cabozantinib, axitinib, lapatinib, and vatalanib to investigate the possible repurposing of these compounds as antiplatelet drugs
We observed that the TKIs with the highest reported affinities for platelet-expressed molecular targets most strongly inhibited platelet function

Summary

Introduction

Ischemic heart disease and stroke accounted for >15 million deaths worldwide in2019, making arterial thrombosis a leading global cause of death [1]. Current treatment is mostly (dual) antiplatelet therapy, such as aspirin and clopidogrel, which prevent thromboxane A2 release and ADP receptor activation, respectively [4]. These inhibitors mostly have an irreversible mode of action on the platelet G-protein coupled receptor (GPCRs)-signaling pathways and coincide with an increased risk of bleeding [5]. Novel antiplatelet drugs are being developed that inhibit thrombosis but do not interfere in hemostasis [5] In this respect, glycoprotein (GP) VI and C-type lectin-like receptor 2 (CLEC-2) receptors, as well as downstream tyrosine kinases, have been postulated as promising antithrombotic targets [6]

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