Anti-Tumor Effects of Gilteritinib on Mutations: Insights into Resistance Mechanisms in Ba/F3 Cell Models.

BACKGROUND

The efficacy of Fms-like tyrosine kinase 3 (FLT3) inhibitors has been well established against acute myeloid leukemia (AML) with internal tandem duplication (-ITD) mutations. However, comparative data on the available inhibitors are limited, and drug resistance remains a major concern.

METHODS

This study examined the inhibitory effects of gilteritinib, quizartinib and midostaurin on Ba/F3 cells with -ITD mutations, or point mutations in the tyrosine kinase domain (TKD-PM) or juxtamembrane domain (JMD-PM), both in vitro and in vivo. Quizartinib and midostaurin were selected as comparators due to their clinical relevance in the AML setting and differing mechanisms of action.

RESULTS

Gilteritinib showed similar or superior growth inhibition against the majority of -TKD-PM or -JMD-PM cells compared to -ITD-mutant cells. In contrast, the inhibitory effects of quizartinib were reduced on cells with most types of -TKD-PM, and the inhibitory effects of midostaurin were attenuated on cells with -TKD-PM N676K. Gilteritinib also effectively suppressed FLT3 autophosphorylation and phosphorylation of signal transducer and activator of transcription 5 (STAT5), AKT and extracellular signal-regulated kinase (ERK) in -TKD-PM cells, while quizartinib showed a reduced inhibitory effect on FLT3 autophosphorylation and phosphorylation of downstream signaling molecules in -TKD-PM cells. In mice xenografted with Ba/F3 cells expressing -ITD mutations or -TKD-PM, gilteritinib showed a potent antitumor effect, whereas the antitumor effect of quizartinib was significantly diminished in the -TKD-PM xenograft model.

CONCLUSION

These findings highlight the potent efficacy of gilteritinib against a wide range of mutations, including TKD-PM and JMD-PM, as well as those associated with resistance to quizartinib or midostaurin. This comparative analysis underscores the need for tailored therapeutic strategies in AML treatment, emphasizing the clinical significance of gilteritinib in overcoming drug resistance.