- Tyrosine kinases mediate response of blood cells to stimuli and small molecule tyrosine kinase inhibitors (TKIs) serve important roles as drugs in managing hematological diseases. In healthy B cells, the B cell receptor (BCR) activates a tyrosine kinase known as Syk, which then activates BTK, PI3K, PLC2 and protein kinase C (PKC) to mediate responses such as cell migration and proliferation. In many hematologic cancer cells, BCRs are overactive, causing an uncontrolled increase in cell survival and proliferation. TKIs against Syk, as well as BTK can block highly active BCR, and restore normal cell function and turnover. In this regard, TKIs have been shown to successfully treat several blood cancers. Unfortunately, many TKI drugs also affect other blood cells, including platelets, and bleeding complications are common to TKI therapy. Here, the effects of specific TKIs on platelet function is investigated. Results show that TKIs targeting components of the same Syk-BTK-PI3K signaling pathway have varying effects on platelet responses. These results suggest that these differential effects may be attributed to altered protein-protein interactions within platelets with Syk and BTK specific inhibitors in a manner that may be relevant to better understanding off-target effects and the toxicity of therapeutic TKIs.
Key Words: Platelet, tyrosine kinase inhibitors (TKIs), Syk, BTK, PI3K