Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations.
Blood
; 123(10): 1516-24, 2014 Mar 06.
Article
em En
| MEDLINE
| ID: mdl-24408322
ABSTRACT
Development of resistance to kinase inhibitors remains a clinical challenge. Kinase domain mutations are a common mechanism of resistance in chronic myeloid leukemia (CML), yet the mechanism of resistance in the absence of mutations remains unclear. We tested proteins from the bone marrow microenvironment and found that FGF2 promotes resistance to imatinib in vitro. Fibroblast growth factor 2 (FGF2) was uniquely capable of promoting growth in both short- and long-term assays through the FGF receptor 3/RAS/c-RAF/mitogen-activated protein kinase pathway. Resistance could be overcome with ponatinib, a multikinase inhibitor that targets BCR-ABL and FGF receptor. Clinically, we identified CML patients without kinase domain mutations who were resistant to multiple ABL kinase inhibitors and responded to ponatinib treatment. In comparison to CML patients with kinase domain mutations, these patients had increased FGF2 in their bone marrow when analyzed by immunohistochemistry. Moreover, FGF2 in the marrow decreased concurrently with response to ponatinib, further suggesting that FGF2-mediated resistance is interrupted by FGF receptor inhibition. These results illustrate the clinical importance of ligand-induced resistance to kinase inhibitors and support an approach of developing rational inhibitor combinations to circumvent resistance.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piridazinas
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Leucemia Mielogênica Crônica BCR-ABL Positiva
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Fator 2 de Crescimento de Fibroblastos
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Resistencia a Medicamentos Antineoplásicos
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Inibidores de Proteínas Quinases
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Domínios e Motivos de Interação entre Proteínas
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Imidazóis
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Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article