Abstract
Overcoming AC220 resistance of FLT3-ITD by SAR302503
Highlights
Activating mutations in FLT3 (Fms-like tyrosine kinase 3) by internal tandem duplication (ITD) mutations are found in approximately 30% of patients with acute myeloid leukemia (AML) and are associated with poor outcome in this patient population
An elegant translational study designed by Neil Shah’s group has identified the AC220 resistant mutations in all FLT3-ITD relapsed patients that definitively demonstrated the validity of FLT3-ITD as a therapeutic target in human AML.[2]
SAR302503 inhibited proliferation of BAF3 cells expressing FLT3 wild type and FLT3-ITD, with IC50 values of 119 and 330 nM, respectively (Figure 1a), whereas parental BAF3 cells and BAF3JAK2-V617F cells were inhibited at IC50 values of B1100 and 600 nM, respectively (Supplementary Figure 1a)
Summary
Activating mutations in FLT3 (Fms-like tyrosine kinase 3) by internal tandem duplication (ITD) mutations are found in approximately 30% of patients with acute myeloid leukemia (AML) and are associated with poor outcome in this patient population. We analyzed the activity of SAR302503 against five different kinase domain variants of FLT3-ITD that had been shown to confer resistance against AC220.
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