Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

Ronan T Swords, C. Freeman, F. Giles

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/ pharmacodynamic profile. Novel combination regimens are also discussed.

Original languageEnglish
Pages (from-to)2176-2185
Number of pages10
JournalLeukemia
Volume26
Issue number10
DOIs
StatePublished - Oct 1 2012

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Receptor Protein-Tyrosine Kinases
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Myeloid Cells
Disease-Free Survival
Up-Regulation
Pharmacokinetics
Ligands
Drug Therapy
Mutation

Keywords

  • Acute myeloid leukemia
  • FLT3
  • Internal tandem duplication
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia. / Swords, Ronan T; Freeman, C.; Giles, F.

In: Leukemia, Vol. 26, No. 10, 01.10.2012, p. 2176-2185.

Research output: Contribution to journalArticle

Swords, RT, Freeman, C & Giles, F 2012, 'Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia', Leukemia, vol. 26, no. 10, pp. 2176-2185. https://doi.org/10.1038/leu.2012.114
Swords, Ronan T ; Freeman, C. ; Giles, F. / Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia. In: Leukemia. 2012 ; Vol. 26, No. 10. pp. 2176-2185.
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