Pharmacological effects of small molecule BCR-ABL tyrosine kinase inhibitors on platelet function.

Abstract

Tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-ABL fusion protein, such as imatinib (Gleevec), have revolutionized targeted cancer therapies. However, drug resistance and side effects, particularly those affecting hemostasis, continue to pose significant challenges for TKI therapies. As tyrosine kinases serve pivotal roles in platelet hemostatic function, we investigated the potential impact of both established and emerging ABL TKIs on human platelet activities ex vivo. Our study included standard-of-care agents (eg, imatinib and nilotinib) and second-generation ABL inhibitors, including ponatinib and bosutinib, designed to mitigate drug resistance. Additionally, we explored the effects of allosteric inhibitors targeting the myristoyl pocket of ABL (eg, asciminib and GNF-2) and novel agents in preclinical development, including ELVN-919, which uniquely exhibits high specificity for the ABL kinase active site. Our findings reveal that while ABL inhibitors such as ponatinib and bosutinib impede platelet activity, highly specific new-generation ABL inhibitors, including first-in-class therapeutics, do not impact platelet function ex vivo. Overall, these new insights around the effects of ABL TKIs on platelet function could inform the development of targeted therapies with reduced hematologic toxicities. SIGNIFICANCE STATEMENT: This study examines the effects of clinically relevant small molecule breakpoint cluster region (BCR)-ABL tyrosine kinase inhibitors (TKIs) on platelet activity. This analysis includes first-time assessments of agents such as asciminib and ELVN-919 on human platelet function ex vivo, alongside established therapies (eg, imatinib, ponatinib) with well characterized effects on platelet function, to discern potential antiplatelet and other effects of BCR-ABL TKIs and inform clinical safety.