Journal
LEUKEMIA
Volume 29, Issue 12, Pages 2390-2392Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.165
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Funding
- National Cancer Institute [1R01 CA166616-01]
- Leukemia and Lymphoma Society
- Hellman Family Foundation Early Career Faculty Award
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Activating mutations in FLT3 occur in similar to 30% of adult acute myeloid leukemia, primarily consisting of internal tandem duplication (ITD) mutations (similar to 25%) and point mutations in the tyrosine kinase domain (similar to 5%), commonly at the activation loop residue D835. Secondary kinase domain mutations in FLT3-ITD, particularly at the D835 residue are frequently associated with acquired clinical resistance to effective FLT3 tyrosine kinase inhibitors (TKIs). Molecular docking studies have suggested that D835 mutations primarily confer resistance by stabilizing an active Asp-Phe-Gly in ('DFG-in') kinase conformation unfavorable to the binding of type II FLT3 TKIs, which target a 'DFG-out' inactive conformation. We profiled the activity of active type II FLT3 TKIs against D835 kinase domain mutants that have been clinically detected to date. We found that type II inhibitors (quizartinib, sorafenib, ponatinib and PLX3397) retain activity against specific D835 substitutions. Modeling studies suggest that bulky hydrophobic substitutions (D835Y/V/I/F) at this residue are particularly resistant, whereas mutations that preserve interactions between D835 and S838 are relatively sensitive (D835E/N). All mutants retain sensitivity to the type I inhibitor crenolanib. These results suggest that patients with relatively sensitive D835 mutations should be included in clinical trials of type II FLT3 TKIs.
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