Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• FMS-like tyrosine kinase 3-internal tandem duplications (FLT3-ITD) are common in acute myeloid leukemia (AML), correlating with poor prognosis.
• Relapsed FLT3-mutated AML shows initial response to FLT3 tyrosine kinase inhibitors (TKIs) but resistance develops rapidly.
• The bone marrow microenvironment contributes to leukemia cell survival and TKI resistance.

Purpose of the Study:

• To investigate the mechanisms of resistance to FLT3 TKIs in FLT3-ITD+ AML.
• To evaluate the efficacy of combining quizartinib with dasatinib in overcoming microenvironment-mediated resistance.

Main Methods:

• FLT3-ITD+ AML cells were cultured in bone marrow-derived conditioned medium (CM).
• Cells were treated with quizartinib alone or in combination with dasatinib.
• STAT3 and STAT5 activation, glycolysis, and cell viability were assessed.
• STAT5 knockdown was performed to investigate its role in resistance.

Main Results:

• CM protected FLT3-ITD+ AML cells from quizartinib, activating STAT3 and STAT5.
• STAT5 activation by CM was identified as a key mediator of quizartinib resistance.
• Combination treatment with quizartinib and dasatinib inhibited STAT5 activation and reduced quizartinib's IC50.
• The combination partially reversed quizartinib's inhibitory effects on glycolysis.

Conclusions:

• The bone marrow microenvironment promotes FLT3-TKI resistance in FLT3-ITD+ AML via STAT5 activation.
• Combination therapy with quizartinib and dasatinib shows preclinical promise for overcoming resistance.
• This combination warrants further investigation for treating relapsed FLT3-ITD+ AML.