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Title

Inhibition of Flt3-activating mutations does not prevent constitutive activation of ERK/Akt/STAT pathways in some AML cells: A possible cause for the limited effectiveness of monotherapy with small-molecule inhibitors

AuthorsSiendones, Emilio CSIC; Barbarroja, Nuria; Arístides Torres, Luis; Buendía, Paula; Velasco, Francisco; Dorado, Gabriel; Torres, Antonio; López-Pedrera, Chary
KeywordsFlt3
Survival
MAP kinases
STAT
AKT
AML
Issue Date2007
PublisherJohn Wiley & Sons
CitationHematological Oncology 25(1): 30-37 (2007)
AbstractThe Flt3 receptor tyrosine kinase is a critical mediator in the pathogenesis of acute myeloid leukaemia (AML). Flt3-activating mutations have been associated with poor prognosis and decreased overall survival of AML patients, thus Flt3 constitutes an ideal target for drug treatment of such disease. Unfortunately, the monotherapy with small-molecule tyrosine kinase inhibitors in clinical trials shows that remission is not permanent, presumably by resistance of Flt3 mutants to inhibitors. An alternative approach for treatment is based on the cooperation between Flt3 and additional intracellular pathways for AML transformation in some patients. Thus, the inhibition of both Flt3 and such pathways may be exploited for successful treatment of the disease. We investigated the importance of Flt3-activating mutations for the constitutive activation of intracellular pathways in primary AML cells, and their effect on cell survival. We found that the main compounds involved in the differentiation, proliferation and survival of AML (MAPK/AKT/STAT) were constitutively activated. However, only four samples showed internal tandem duplications (ITDs) for Flt3. Surprisingly, contrary to previous reports, we found that inhibition of ITD/Flt3 activity did not prevent the phosphorylation of ERK, STAT5 or Akt in some primary AML cells. In parallel, we found that in these cells, Flt3 and ERK or Akt cooperate to regulate cell survival. Our results support the hypothesis that the optimal therapeutic treatment of AML may require not only the oncogenic tyrosine kinase, but also the appropriate combination of different specific inhibitors, thus providing a more effective approach to reverse leukaemogenesis. Thus, we propose that each AML patient should have an individually tailored combination treatment.
Publisher version (URL)http://dx.doi.org/10.1002/hon.805
URIhttp://hdl.handle.net/10261/198772
DOI10.1002/hon.805
Identifiersdoi: 10.1002/hon.805
issn: 0278-0232
e-issn: 1099-1069
Appears in Collections:(CABD) Artículos




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