Abstract 1248: Ibrutinib inhibits platelet aggregation through inhibition of mitochondrial respiratory chain function and suppression of Syk activation

Abstract

Abstract Ibrutinib represents a therapeutic improvement in hematologic cancers, but it is associated with bleeding-related adverse events. To minimize such adverse events and improve the therapeutic utility of this drug, it is important to understand the underlying mechanisms responsible for the adverse events. In this study, we observed that platelets isolate from the blood samples of chronic lymphocytic leukemia (CLL) treated with Ibrutinib exhibited deficiencies in collagen-mediated aggregation. Mechanistic studies identified the mitochondrial respiratory chain as a potential mediator of ibrutinib-induced impairment of platelet function. A short-term treatment of platelets isolated from human blood with ibrutinib for less than one hour led to reactive oxygen species (ROS) generation associated with inhibition of mitochondrial respiration, as evident by a reduction in oxygen consumption rate measured by a Seahorse metabolic analyser. Long-term incubation of megakaryocytes with ibrutinib markedly suppressed the expression of mitochondrial electron transport chain components in platelets and a reduction in mitochondrial respiration. Interference with the respiratory chain by rotenone also resulted in similar reduction in collagen-induced platelet aggregation. Interestingly, ROS generation upon collagen stimulation induced tyrosine phosphorylation of Syk (spleen tyrosine kinase) to activate platelet, while impairment of respiratory chain induced by ibrutinib diminished collagen-evoked activation of the Syk pathway. These data suggest that ibrutinib suppresses mitochondrial respiration, leading to defects in collagen-induced platelet aggregation, potentially through inhibiting the activation of the Syk pathway. Citation Format: Jie Huang, Helen Pelicano, Feng Li, Michael J. Keating, Peng Huang. Ibrutinib inhibits platelet aggregation through inhibition of mitochondrial respiratory chain function and suppression of Syk activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1248.