FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-07-16

AUTHORS

A Y H Leung, C-H Man, Y-L Kwong

ABSTRACT

Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene is a gain-of-function mutation common in acute myeloid leukaemia (AML). It is associated with inferior prognosis and response to chemotherapy. Single base mutations at the FLT3 tyrosine kinase domain (TKD) also leads to a gain of function, although its prognostic significance is less well defined because of its rarity. The clinical benefits of FLT3 inhibition are generally limited to AML with FLT3-ITD. However, responses are transient and leukaemia progression invariably occurs. There is compelling evidence that leukaemia clones carrying both ITD and TKD mutations appear when resistance to FLT3 inhibitors occurs. Interestingly, the emergence of double ITD and TKD mutants can be recapitulated in vitro when FLT3-ITD+ leukaemia cell lines are treated with mutagens and FLT3 inhibitors. Furthermore, murine xenotransplantation models also suggest that, in some cases, the FTL3-ITD and TKD double mutants actually exist in minute amounts before treatment with FLT3 inhibitors, expand under the selection pressure of FLT3 inhibition and become the predominant resistant clone(s) during the drug-refractory phase. On the basis of this model of clonal evolution, a multipronged strategy using more potent FLT3 inhibitors, and a combinatorial approach targeting both FLT3-dependent and FLT3-independent pathways, will be needed to improve outcome. More... »

PAGES

260-268

References to SciGraph publications

  • 2011-12-20. BPR1J-097, a novel FLT3 kinase inhibitor, exerts potent inhibitory activity against AML in BRITISH JOURNAL OF CANCER
  • 2005-08-01. Signal Transduction of Oncogenic Flt3 in INTERNATIONAL JOURNAL OF HEMATOLOGY
  • 2012-02-22. Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns in LEUKEMIA
  • 2011-03-01. Discovery of LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem duplication mutant human tumor xenograft model in INVESTIGATIONAL NEW DRUGS
  • 2010-06-03. Identification of a secondary FLT3/A848P mutation in a patient with FLT3-ITD-positive blast phase CMML and response to sunitinib and sorafenib in LEUKEMIA
  • 2012-04-15. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia in NATURE
  • 2007-03-01. AS602868, a dual inhibitor of IKK2 and FLT3 to target AML cells in LEUKEMIA
  • 2009-10-15. Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis in LEUKEMIA
  • 2003. Prognostic significance of FLT3 ITD and D835 mutations in AML patients. in HAEMATOLOGICA
  • 2006-10-01. Synergistic Effect of Arsenic Trioxide and Flt3 Inhibition on Cells with Flt3 Internal Tandem Duplication in INTERNATIONAL JOURNAL OF HEMATOLOGY
  • 2012-01-18. Clonal evolution in cancer in NATURE
  • 2005-08-01. Clinical Significance of FLT3 in Leukemia in INTERNATIONAL JOURNAL OF HEMATOLOGY
  • 2010-07-12. Drug resistance in mutant FLT3-positive AML in ONCOGENE
  • 2010-06-10. A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias in LEUKEMIA
  • 2012-04-03. Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors and JAK inhibitors in LEUKEMIA
  • 2012-04-27. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia in LEUKEMIA
  • 2012-01-09. Novel targeted therapy for acute myeloid leukemia with a dual FLT3 and JAK2 inhibitor in ACTA PHARMACOLOGICA SINICA
  • 2010-02-11. Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias in LEUKEMIA
  • 1998-09-01. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product in LEUKEMIA
  • 2011-08-23. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties in LEUKEMIA
  • 2010-01-30. Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells in ANNALS OF HEMATOLOGY
  • 2012-03-09. SKLB1028, a novel oral multikinase inhibitor of EGFR, FLT3 and Abl, displays exceptional activity in models of FLT3-driven AML and considerable potency in models of CML harboring Abl mutants in LEUKEMIA
  • 2008-09-11. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions in NATURE REVIEWS CANCER
  • 2012-04-16. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses in LEUKEMIA
  • 1997-09-01. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia in LEUKEMIA
  • 2003-09. The role of FLT3 in haematopoietic malignancies in NATURE REVIEWS CANCER
  • 2012-01-11. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing in NATURE
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    http://scigraph.springernature.com/pub.10.1038/leu.2012.195

    DOI

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    38 schema:description Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene is a gain-of-function mutation common in acute myeloid leukaemia (AML). It is associated with inferior prognosis and response to chemotherapy. Single base mutations at the FLT3 tyrosine kinase domain (TKD) also leads to a gain of function, although its prognostic significance is less well defined because of its rarity. The clinical benefits of FLT3 inhibition are generally limited to AML with FLT3-ITD. However, responses are transient and leukaemia progression invariably occurs. There is compelling evidence that leukaemia clones carrying both ITD and TKD mutations appear when resistance to FLT3 inhibitors occurs. Interestingly, the emergence of double ITD and TKD mutants can be recapitulated in vitro when FLT3-ITD+ leukaemia cell lines are treated with mutagens and FLT3 inhibitors. Furthermore, murine xenotransplantation models also suggest that, in some cases, the FTL3-ITD and TKD double mutants actually exist in minute amounts before treatment with FLT3 inhibitors, expand under the selection pressure of FLT3 inhibition and become the predominant resistant clone(s) during the drug-refractory phase. On the basis of this model of clonal evolution, a multipronged strategy using more potent FLT3 inhibitors, and a combinatorial approach targeting both FLT3-dependent and FLT3-independent pathways, will be needed to improve outcome.
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    46 FLT3 inhibitors
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    60 clonal evolution
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    66 duplication
    67 emergence
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    70 fms-like tyrosine kinase 3 (FLT3) gene
    71 function
    72 function mutations
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    75 genes
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    77 inhibition
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    87 model
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    89 mutagens
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