Key role of glutamine metabolism in persistence of leukemic cells upon exposition to FLT3 tyrosine kinase inhibitors.
Exp Hematol
; 137: 104253, 2024 Sep.
Article
em En
| MEDLINE
| ID: mdl-38879112
ABSTRACT
Acute myeloid leukemias are a group of hematological malignancies characterized by a poor prognosis for survival. The discovery of oncogenic mutations in the FMS-like tyrosine kinase 3 (FLT3) gene has led to the development of tyrosine kinase inhibitors such as quizartinib. However, achieving complete remission in patients remains challenging because these new tyrosine kinase inhibitors (TKIs) are unable to completely eradicate all leukemic cells. Residual leukemic cells persist during quizartinib treatment, leading to the rapid emergence of drug-resistant leukemia. Given that mitochondrial oxidative metabolism promotes the survival of leukemic cells after exposure to multiple anticancer drugs, we characterized the metabolism of leukemic cells that persisted during quizartinib treatment and developed metabolic strategies to eradicate them. In our study, employing biochemical and metabolomics approaches, we confirmed that the survival of leukemic cells treated with FLT3 inhibitors critically depends on maintaining mitochondrial metabolism, specifically through glutamine oxidation. We uncovered a synergistic interaction between the FLT3 inhibitor quizartinib and L-asparaginase, operating through antimetabolic mechanisms. Utilizing various models of persistent leukemia, we demonstrated that leukemic cells resistant to quizartinib are susceptible to L-asparaginase. This combined therapeutic strategy shows promise in reducing the development of resistance to FLT3 inhibitors, offering a potential strategy to enhance treatment outcomes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos de Fenilureia
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Leucemia Mieloide Aguda
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Inibidores de Proteínas Quinases
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Tirosina Quinase 3 Semelhante a fms
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Glutamina
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article