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.

• Authors: Cassandra P Loren, Joseph E Aslan, Rachel A Rigg, Marie S Nowak, Laura D Healy, András Gruber, Brian J Druker, Owen J T McCarty
• Journal: Thrombosis research (Thromb Res) Vol. 135 Issue 1 Pg. 155-60 (Jan 2015) ISSN: 1879-2472 [Electronic] United States
• PMID: 25527332 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Imidazoles
• P-Selectin
• Phosphatidylserines
• Pyridazines
• Tyrosine
• ponatinib
• Fibrinogen
• Collagen
• Fusion Proteins, bcr-abl

Topics

• Amino Acid Motifs
• Apoptosis
• Blood Platelets (cytology, drug effects)
• Collagen (chemistry)
• Endothelial Cells (cytology)
• Fibrinogen (chemistry)
• Fusion Proteins, bcr-abl (antagonists & inhibitors)
• Humans
• Imidazoles (antagonists & inhibitors)
• Immunoreceptor Tyrosine-Based Activation Motif
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism)
• P-Selectin (chemistry)
• Phosphatidylserines (chemistry)
• Phosphorylation
• Platelet Activation
• Platelet Aggregation
• Pyridazines (antagonists & inhibitors)
• Shear Strength
• Signal Transduction
• Tyrosine (chemistry)