title: 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
  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.
  
  
  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.affiliation: Department of Biomedical Engineering; Department of Cell & Developmental Biology. Electronic address: cassandraloren@gmail.com.
authors.forename: Cassandra P
authors.initials: CP
authors.lastname: Loren
authors.affiliation: Department of Biomedical Engineering; Department of Cell & Developmental Biology.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Aslan
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Rigg
authors.affiliation: Department of Biomedical Engineering; Department of Medical Physics, Universite des Sciences et Technologies de Lille, Villeneuve d'Ascq Cedex, France.
authors.forename: Marie S
authors.initials: MS
authors.lastname: Nowak
authors.affiliation: Department of Cell & Developmental Biology.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Healy
authors.affiliation: Department of Biomedical Engineering; Division of Hematology & Medical Oncology, School of Medicine.
authors.forename: András
authors.initials: A
authors.lastname: Gruber
authors.affiliation: Division of Hematology & Medical Oncology, School of Medicine; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Howard Hughes Medical Institute, Portland, OR, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Department of Biomedical Engineering; Department of Cell & Developmental Biology; Division of Hematology & Medical Oncology, School of Medicine.
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
mesh_terms: D020816:Amino Acid Motifs; D017209:Apoptosis; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D003094:Collagen / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology; D005340:Fibrinogen / Q000737:chemistry; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000037:antagonists & inhibitors*; D061625:Immunoreceptor Tyrosine-Based Activation Motif; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism; D019007:P-Selectin / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D010766:Phosphorylation; D015539:Platelet Activation; D010974:Platelet Aggregation; D011724:Pyridazines / Q000037:antagonists & inhibitors*; D033081:Shear Strength; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry
chemical_list: D007093:Imidazoles; D019007:P-Selectin; D010718:Phosphatidylserines; D011724:Pyridazines; D014443:Tyrosine; C545373:ponatinib; D005340:Fibrinogen; D003094:Collagen; D016044:Fusion Proteins, bcr-abl
keywords: Chronic Myelogenous Leukemia; Platelets; Thrombosis; Tyrosine Kinase