The BCR-ABL inhibitor ponatinib inhibits platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling, platelet activation and aggregate formation under shear

Abstract

Background Treatment of chronic myelogenous leukemia (CML) with the BCR-ABL tyrosine kinase inhibitor (TKI) imatinib significantly improves patient outcomes. As some patients are unresponsive to imatinib, next generation BCR-ABL inhibitors such as nilotinib have been developed to treat patients with imatinib-resistant CML. The use of some BCR-ABL inhibitors has been associated with bleeding diathesis, and these inhibitors have been shown to inhibit platelet functions, which may explain the hemostasis impairment. Surprisingly, a new TKI, ponatinib, has been associated with a high incidence of severe acute ischemic cardiovascular events. The mechanism of this unexpected adverse effect remains undefined. Objective and Methods This study used biochemical and functional assays to evaluate whether ponatinib was different from the other BCR-ABL inhibitors with respect to platelet activation, spreading, and aggregation. Results and Conclusions Our results show that ponatinib, similar to other TKIs, acts as a platelet antagonist. Ponatinib inhibited platelet activation, spreading, granule secretion, and aggregation, likely through broad spectrum inhibition of platelet tyrosine kinase signaling, and also inhibited platelet aggregate formation in whole blood under shear. As our results indicate that pobatinib inhibits platelet function, the adverse cardiovascular events observed in patients taking ponatinib may be the result of the effect of ponatinib on other organs or cell types or disease-specific processes, such as BCR-ABL+ cells undergoing apoptosis in response to chemotherapy, or drug-induced adverse effects on the integrity of the vascular endothelium in ponatinib-treated patients.

Acquired platelet antagonism: off‐target antiplatelet effects of malignancy treatment with tyrosine kinase inhibitors

“…The use of ponatinib has been associated with bleeding diatheses, along with changes in platelet count and function, which may explain the impaired hemostasis . One study described inhibitory effects of ponatinib, imatinib and nilotinib on platelet activation, secretion and aggregation in response to collagen . In this study, ponatinib appeared to be the most potent platelet inhibitor.…”

“…In this study, ponatinib appeared to be the most potent platelet inhibitor. Ponatinib increased PFA‐100 closure times, probably by suppressing ITAM signaling via several tyrosine kinases, including Src, Lyn, Syk, and Btk . In contrast, imatinib and nilotinib did not affect platelet granule secretion, procoagulant activity, or aggregation, and only moderately reduced the tyrosine phosphorylation of Lyn and Btk as compared with ponatinib .…”

Ponatinib treatment promotes arterial thrombosis and hyperactive platelets

“…In previous in vitro investigations, CRP-induced, but not thrombininduced, platelet activation was inhibited by treating washed platelets with 100 nM of ponatinib. 14 In our studies, platelets were exposed to lower in vivo ponatinib concentrations (2-33 nM; Table 1). These platelets were hyperreactive when treated with similar concentrations of CRP and a-thrombin.…”

Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial

“…†See supplemental 32 or the plasma lipid profile. 33 Ponatinib inhibits vascular endothelial growth factor receptors and other targets known to regulate vascular homeostasis (TIE2, platelet-derived growth factor receptors, fibroblast growth factor receptors, and ephrin receptor family members), but the effect on AOEs is unknown.…”