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

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.

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Old Tyrosine Kinase Inhibitors and Newcomers in Gastrointestinal Cancer Treatment

Current Cancer Drug Targets ◽

10.2174/1568009615666150817120712 ◽

2016 ◽

Vol 16 (2) ◽

pp. 175-185 ◽

Cited By ~ 5

Author(s):

Giordani Erika ◽

Zoratto Federica ◽

Strudel Martina ◽

Papa Anselmo ◽

Rossi Luigi ◽

...

Keyword(s):

Tyrosine Kinase ◽

Cancer Treatment ◽

Tyrosine Kinase Inhibitors ◽

Gastrointestinal Cancer ◽

Kinase Inhibitors

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Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque–triggered thrombus formation in humans

Blood ◽

10.1182/blood-2017-09-808808 ◽

2018 ◽

Vol 131 (24) ◽

pp. 2605-2616 ◽

Cited By ~ 30

Author(s):

Kristina Busygina ◽

Janina Jamasbi ◽

Till Seiler ◽

Hans Deckmyn ◽

Christian Weber ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Atherosclerotic Plaque ◽

Kinase Inhibitors ◽

Thrombus Formation ◽

Drug Dosing ◽

Key Points ◽

Bruton Tyrosine Kinase ◽

Platelet Thrombus ◽

Btk Inhibitors

Key Points Btk inhibitors specifically block platelet thrombus formation on atherosclerotic plaque but spare physiologic hemostasis. Irreversible Btk inactivation in platelets incapable of enzyme resynthesis allows low intermittent drug dosing for antiatherothrombosis.

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Tyrosine kinase inhibitors in cancer treatment (Part II)

Expert Opinion on Therapeutic Patents ◽

10.1517/13543776.8.12.1599 ◽

1998 ◽

Vol 8 (12) ◽

pp. 1599-1625 ◽

Cited By ~ 49

Author(s):

Peter Traxler

Keyword(s):

Tyrosine Kinase ◽

Cancer Treatment ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors

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Thrombin Mediated Tyrosine Phosphorylation of PKCδ in Human Platelets Occurs in a Calcium- and Src Family Tyrosine Kinase- Dependent Manner.

Blood ◽

10.1182/blood.v104.11.3541.3541 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3541-3541

Author(s):

Swaminathan Murugappan ◽

Haripriya Shankar ◽

Satya Kunapuli

Keyword(s):

Tyrosine Kinase ◽

Intracellular Calcium ◽

Tyrosine Phosphorylation ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Human Platelets ◽

Dependent Manner ◽

Protein Signaling ◽

Glycoprotein Vi ◽

Pkc Isoforms

Abstract Protein kinase C (PKC)-δ is a novel PKC that has been shown to be tyrosine phosphorylated upon stimulation with agonists in platelets. Tyrosine phosphorylation of PKCδ has been shown to occur in a Fyn-dependent manner downstream of glycoprotein VI (GPVI) signaling in platelets. Although thrombin causes tyrosine phosphorylation of PKCδ in platelets, the mechanism of this event is not elucidated. In this study, we investigated whether G-protein signaling pathways utilize similar pathways as GPVI in tyrosine phosphorylation of PKCδ. Protease activated receptor (PAR) -1 selective peptide, SFLLRN and PAR - 4 selective peptide, AYPGKF caused a time- and concentration-dependent increase in tyrosine phosphorylation of PKCδ in human platelets. However, AYPGKF failed to cause tyrosine phosphorylation of PKCδ in Gq-deficient mouse platelets. Both U73122, a phospholipase C (PLC) inhibitor, and dimethyl-BAPTA, an intracellular calcium chelator, inhibited the tyrosine phosphorylation of PKCδ downstream of the PAR activation suggesting a role for Gq/PLC pathways and intracellular calcium in mediating this event. Inhibition of PKC isoforms using GF109203X potentiated the tyrosine phosphorylation of PKCδ. The Src family tyrosine kinase inhibitors, PP1 and PP2 inhibited the tyrosine phosphorylation of PKCδ suggesting a role for Src family tyrosine kinase members in this event. We also found that both Lyn and Src are physically associated with PKCδ in a constitutive manner in platelets. Finally we found that there was a time-dependent activation of Src following activation of platelets with thrombin. Thus, the precomplexed Src and Lyn tyrosine kinases get activated following PAR stimulation resulting in the tyrosine phosphorylation of PKCδ. All these data indicate that tyrosine phosphorylation of PKCδ downstream of thrombin occurs in a calcium- and Src-family kinase dependent manner in human platelets.

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Target prices for mass production of tyrosine kinase inhibitors for global cancer treatment

BMJ Open ◽

10.1136/bmjopen-2015-009586 ◽

2016 ◽

Vol 6 (1) ◽

pp. e009586 ◽

Cited By ~ 33

Author(s):

Andrew Hill ◽

Dzintars Gotham ◽

Joseph Fortunak ◽

Jonathan Meldrum ◽

Isabelle Erbacher ◽

...

Keyword(s):

Tyrosine Kinase ◽

Cancer Treatment ◽

Tyrosine Kinase Inhibitors ◽

Mass Production ◽

Kinase Inhibitors

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Individual Variation in Hemostatic Alterations Caused By Tyrosine Kinase Inhibitors - a Way to Improve Personalized Cancer Therapy?

Blood ◽

10.1182/blood.v128.22.1908.1908 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1908-1908

Author(s):

Kourosh Lotfi ◽

Suryyani Deb ◽

Clara Sjöström ◽

Anjana Tharmakulanathan ◽

Niklas Boknäs ◽

...

Keyword(s):

Platelet Aggregation ◽

Side Effects ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Platelet Function ◽

Thrombin Generation ◽

Kinase Inhibitors ◽

Thrombus Formation ◽

Individual Variations

Abstract Introduction During the last two decades, Bcr-Abl tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myelogenous leukemia (CML), and are now considered standard treatment for this disease. However, TKIs can induce serious hemostatic side effects including cardiovascular disease and bleeding disorders. Blood platelet aggregation and formation of pro-coagulant platelets are important to allow a well-balanced hemostatic response. Therefore, a detailed understanding of what effect different TKIs exert on platelets and hemostasis could help to understand if there are differences of importance to minimize the risk of bleeding complications in treated patients. Aim To investigate how TKIs used in CML (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) affect platelet activation and hemostasis. Materials and Methods We have developed a multi-parameter six color flow cytometry protocol to study different aspects of platelet function upon activation, e.g. formation of aggregatory (PAC-1-positive) and pro-coagulant (phosphatidylserine-exposing) platelets, exocytosis of alpha- and lysosomal granules and mitochondrial membrane potential.This protocol was performed in presence or absence of TKIs in blood from normal donors and in treated patients. Whole blood aggregometry (Multiplate®), thrombin generation in platelet-rich plasma and in vitro thrombus formation by free oscillation rheometry (ReoRox G2) was further evaluated in some situations. Results At clinically relevant concentrations, dasatinib significantly decreased the formation of procoagulant platelets. Ponatinib induced a slight decrease in formation of procoagulant platelets, whereas bosutinib and nilotinib showed opposite tendencies (n=7). Dasatinib also decreased platelet aggregation (n=4-6) and in vitro thrombus formation (n=3). Thrombin generation was not significantly affected by therapeutic levels of TKIs, whereas higher doses of dasatinib, bosutinib, ponatinib and imatinib significantly changed one or several of the thrombin generation parameters (n=7-8). Interestingly, large differences in response to the drugs were observed among the healthy donors, especially for dasatinib and bosutinib. Major inter-individual variations were also observed in dasatinib-treated patients. Conclusions Different TKIs show varying potency to affect platelet-based hemostasis. In addition, we found large inter-individual variations in how some drugs affected platelet function. Therefore, we suggest that development of a clinically useful protocol for platelet function testing could help to identify patients more susceptible to adverse drug reactions. Such a protocol could potentially help clinicians to gain insight into the risk of side effects, which could help to choose the most suitable drug for each individual patient. Disclosures No relevant conflicts of interest to declare.

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