Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD-transformed hematopoietic cells.

Abstract	Activating mutations in the juxtamembrane domain (FLT3-length mutations, FLT3-LM) and in the protein tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD) represent the most frequent genetic alterations in acute myeloid leukemia (AML) and define a molecular target for therapeutic interventions by protein tyrosine kinase (PTK) inhibitors. We could show that distinct activating FLT3-TKD mutations at position D835 mediate primary resistance to FLT3 PTK inhibitors in FLT3-transformed cell lines. In the presence of increasing concentrations of the FLT3 PTK inhibitor SU5614, we generated inhibitor resistant Ba/F3 FLT3-internal tandem duplication (ITD) cell lines (Ba/F3 FLT3-ITD-R1-R4) that were characterized by a 7- to 26-fold higher IC50 (concentration that inhibits 50%) to SU5614 compared with the parental ITD cells. The molecular characterization of ITD-R1-4 cells demonstrated that specific TKD mutations (D835N and Y842H) on the ITD background were acquired during selection with SU5614. Introduction of these dual ITD-TKD, but not single D835N or Y842H FLT3 mutants, in Ba/F3 cells restored the FLT3 inhibitor resistant phenotype. Our data show that preexisting or acquired mutations in the PTK domain of FLT3 can induce drug resistance to FLT3 PTK inhibitors in vitro. These findings provide a molecular basis for the evaluation of clinical resistance to FLT3 PTK inhibitors in patients with AML.
Authors	Ksenia Bagrintseva, Ruth Schwab, Tobias M Kohl, Susanne Schnittger, Sabine Eichenlaub, Joachim W Ellwart, Wolfgang Hiddemann, Karsten Spiekermann
Journal	Blood (Blood) Vol. 103 Issue 6 Pg. 2266-75 (Mar 15 2004) ISSN: 0006-4971 [Print] United States
PMID	14604974 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	6,7-dimethoxy-2-phenylquinoxaline Antimetabolites, Antineoplastic Antineoplastic Agents DNA-Binding Proteins Enzyme Inhibitors Indoles Milk Proteins Proto-Oncogene Proteins STAT5 Transcription Factor SU 5614 Trans-Activators Tyrphostins Cytarabine Genistein FLT3 protein, human Receptor Protein-Tyrosine Kinases fms-Like Tyrosine Kinase 3 Staurosporine midostaurin
Topics	Acute Disease Animals Antimetabolites, Antineoplastic (pharmacology) Antineoplastic Agents (pharmacology) Apoptosis (drug effects, physiology) Cell Division (drug effects, physiology) Cell Line, Transformed (drug effects, physiology) Cytarabine (pharmacology) DNA-Binding Proteins (metabolism) Drug Resistance, Neoplasm Enzyme Inhibitors (pharmacology) Genistein (pharmacology) Humans Indoles (pharmacology) Leukemia, Myeloid MAP Kinase Signaling System (physiology) Milk Proteins Mutagenesis Phenotype Phosphorylation (drug effects) Protein Structure, Tertiary Proto-Oncogene Proteins (chemistry, genetics, metabolism) Receptor Protein-Tyrosine Kinases (chemistry, genetics, metabolism) STAT5 Transcription Factor Staurosporine (analogs & derivatives, pharmacology) Trans-Activators (metabolism) Tyrphostins (pharmacology) fms-Like Tyrosine Kinase 3

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