Research Papers:
FLT3 activating mutations display differential sensitivity to multiple tyrosine kinase inhibitors
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Abstract
Bao Nguyen1,*, Allen B. Williams1,*, David J. Young1,2, Hayley Ma1, Li Li1, Mark Levis1, Patrick Brown1,2 and Donald Small1,2
1 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Department of Pediatrics Johns Hopkins University School of Medicine, Baltimore, MD, USA
* These authors have contributed equally to this work
Correspondence to:
Donald Small, email:
Keywords: acute myeloid leukemia, mutant FLT3, activation loop, tyrosine kinase inhibitors
Received: December 16, 2016 Accepted: December 25, 2016 Published: January 06, 2017
Abstract
Fms-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase that normally functions in hematopoietic cell survival, proliferation and differentiation. Constitutively activating mutations of FLT3 map predominately to the juxtamembrane domain (internal tandem duplications; ITD) or the activation loop (AL) of the kinase domain and are detected in about 1/3 of de novo acute myeloid leukemia (AML) patients. Small molecule tyrosine kinase inhibitors (TKI) effectively target FLT3/ITD mutations, but some activating mutations, particularly those on the AL, are relatively resistant to many FLT3 TKI. We reproduced many of the AL or other non-ITD activating mutations and tested 13 FLT3 TKI for their activity against these and wild-type FLT3. All 13 TKI tested inhibited BaF3/ITD cell proliferation in a concentration-dependent manner as reported, but most TKI exhibited a wide range of differential activity against AL and other point mutants. Western blotting results examining inhibition of FLT3 autophosphorylation and signaling pathways indicate that many AL mutations reduce TKI binding. Most FLT3 TKI effectively target wild-type FLT3 signaling. As a demonstration of this differential activity, treatment of BaF3 D835Y cells transplanted in BALB/c mice with sorafenib showed no effect in vivo against this mutant whereas lestaurtinib proved effective at reducing disease burden. Thus, while FLT3 TKI have been selected based on their ability to inhibit FLT3/ITD, the selection of appropriate TKI for AML patients with FLT3 AL and other activating point mutations requires personalized consideration.
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