Gilteritinib Reduces FLT3 Expression in Acute Myeloid Leukemia Cells

Acute myeloid leukemia (AML) is a genetically diverse and challenging malignancy, with mutations in the FLT3 gene being particularly common and deleterious.Gilteritinib, a potent FLT3 inhibitor, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory AML with FLT3 mutations.Although gilteritinib was developed based on its inhibitory activity against FLT3 kinase, it is important to understand the precise mechanisms of its antileukemic activity in managing drug resistance and discovering biomarkers.This study was designed to elucidate the effect of gilteritinib on the FLT3 expression level.The results showed that gilteritinib induced a dose-dependent decrease in both FLT3 phosphorylation and expression.This reduction was particularly pronounced after 48 h of treatment.The decrease in FLT3 expression was found to be independent of changes in FLT3 mRNA transcription, suggesting post-transcriptional regulatory mechanisms.Further studies were performed in various AML cell lines and cells with both FLT3 wild-type and FLT3 mutant exhibited FLT3 reduction by gilteritinib treatment.In addition, other FLT3 inhibitors were evaluated for their ability to reduce FLT3 expression.Other FLT3 inhibitors, midostaurin, crenolanib, and quizartinib, also reduced FLT3 expression, consistent with the effect of gilteritinib.These findings hold great promise for optimizing gilteritinib treatment in AML patients.However, it is important to recognize that further research is warranted to gain a full understanding of these mechanisms and their clinical implications in the context of FLT3 reduction.