Inhibition of c-Kit by tyrosine kinase inhibitors

Several small molecule tyrosine kinase inhibitors (TKIs) inhibit c-Kit, an effect associated with myelosuppression and hair depigmentation. We studied a panel of approved and investigational TKIs for inhibitory activity against FLT3 and c-Kit, and on hematopoietic progenitor cells. Potent c-Kit inhibitors such as dasatinib, pazopanib, and quizartinib demonstrated the greatest disruption of hematopoietic progenitor cells, while sorafenib, which has negligible activity against c-Kit, demonstrated only minimal disruption. Our data highlight the importance of determining a therapeutic index between the targeted receptor and c-Kit for TKIs used to treat malignancies in order to maintain normal hematopoiesis and improve outcomes.