Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges

  title={Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges},
  author={David W. Sternberg and Jonathan D. Licht},
  journal={Current Opinion in Hematology},
Purpose of reviewThe fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is now recognized to be a critical mediator in the pathogenesis of myeloid and some lymphoid leukemias. This article reviews recent efforts to disrupt FLT3 signaling in acute myelogenous leukemia and to identify potential therapeutic challenges posed by the acquisition of resistance mutations in these malignancies. Recent findingsSeveral broad classes of FLT3 protein tyrosine kinase inhibitors are undergoing… 
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G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia.
G-749 appears to be a promising next-generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT 3-TKD mutants and further shows the ability to overcome drug resistance.
KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation.
Results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.
PRL-3, a Metastasis Associated Tyrosine Phosphatase, Is Involved in FLT3-ITD Signaling and Implicated in Anti-AML Therapy
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    Expert opinion on emerging drugs
  • 2005
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The clinical and biological consequences of different FLT3 mutations in patients with AML
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ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside
In vitro studies on ABT-869 resistance phenotype identified novel resistance mechanism that may be applicable to other TKIs and the future therapeutic roles of ABT -869 are currently been tested in phase II trials.
Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease
Transgenic mice expressing constitutively activated Tel-FLT3 develop MPD with a long latency and also result in the expansion of the hematopoietic stem/progenitor cells.
Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas.
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Prognostic significance and detection of the internal tandem duplication of the FLT3 gene in acute myeloid leukemia.
The authors purpose was to work out a method for FLT3/ITD detection, which can be used in routine diagnostics, and all samples produced detectable PCR products, which proofs that this procedure could be used for the detection of FLT 3/ITd mutations in daily clinical practice.


Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs.
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  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2004
The mTOR inhibitor rapamycin synergizes with Imatinib against BCR/ABL-transformed myeloid and lymphoid cells and increases survival in a murine CML model, suggesting that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and/or acute myelogenous leukemia caused by FLT3 mutations.
Prediction of Resistance to Small Molecule FLT3 Inhibitors
An in vitro screen designed to identify mutations in the ATP-binding pocket of FLT3 that confer resistance to tyrosine kinase inhibitors indicates that the G697R mutation may be a clinically problematic resistance mutation that warrants proactive screening for additional inhibitors.
SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo.
The in vivo efficacy of SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model, suggesting that further exploration of SU 11248 activity in AML patients is warranted.
Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor
In transfected Ba/F3 cells, AG1296 selectively and potently inhibited autophosphorylation of FL-stimulated wild-type and constitutively activated FLT3, demonstrating that the inhibition is specific to theFLT3 pathway in that it leaves the kinases of the IL-3 pathway and other kinases further downstream involved in proliferation intact.
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FLT3 and its Role in the Pathogenesis of Acute Myeloid Leukaemia
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FLT3, a tyrosine kinase receptor class III (RTK), and its ligand (FL) are important for normal haematopoiesis and the development of the immune system and already phase I clinical trials have been initiated.
SU 11248 is a novel FLT 3 tyrosine kinase inhibitor with potent activity in vitro and in vivo
It is shown that SU11248 (20mg/kg/day) dramatically regresses FLT3-ITD tumors in the SC tumor xenograft model and prolongs survival in the bone marrow engraftment model, and Pharmacokinetic and pharmacodynamic analysis in SC tumors showed that a single administration of an efficacious drug dose potently inhibits FLT 3- ITD phosphorylation for up to 16 hours following a single dose.
A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo.
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