Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling.
Br J Haematol
; 141(4): 483-93, 2008 May.
Article
em En
| MEDLINE
| ID: mdl-18373709
ABSTRACT
Activating mutations of the FMS-like tyrosine kinase 3 gene (FLT3) occur in approximately one-third of patients with acute myeloid leukaemia (AML) and predict for a poor outcome. Heat shock protein 90 (Hsp90) is a molecular chaperone that is frequently used by cancer cells to stabilise mutant oncoproteins. Mutant FLT3 is chaperoned by Hsp90 in primary AML blasts whereas unmutated FLT3 is not, making Hsp90 inhibitors potentially useful therapeutically. The present study showed that inhibition of Hsp90 by 17-allylamino-17-demethoxygeldanamycin (17-AAG) was cytotoxic to primary AML cells expressing mutant FLT3. Inhibition of Hsp90 results in altered downstream signalling effects in primary AML cells with disruption of Janus kinase-signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase and phosphatidylinositol 3/AKT signalling pathways. Co-treatment of blasts with 17-AAG and cytarabine resulted in a synergistic or additive effect in approximately 50% of AML cases tested. Our results confirm that Hsp90 is a valid molecular target in the therapy of AML. Inhibition of Hsp90 in parallel with conventional AML therapies may have particular benefit in those patients with the poor prognostic FLT3 mutant disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
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Benzoquinonas
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Proteínas de Choque Térmico HSP90
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Lactamas Macrocíclicas
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Tirosina Quinase 3 Semelhante a fms
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Antineoplásicos
Tipo de estudo:
Clinical_trials
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Prognostic_studies
Limite:
Adolescent
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Adult
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Aged
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Humans
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Middle aged
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article