The acquisition order of leukemic drug resistance mutations is directed by the selective fitness associated with each resistance mechanism.
Sci Rep
; 13(1): 13110, 2023 08 11.
Article
em En
| MEDLINE
| ID: mdl-37567965
ABSTRACT
In Chronic Myeloid Leukemia, the transition from drug sensitive to drug resistant disease is poorly understood. Here, we used exploratory sequencing of gene transcripts to determine the mechanisms of drug resistance in a dasatinib resistant cell line model. Importantly, cell samples were collected sequentially during drug exposure and dose escalation, revealing several resistance mechanisms which fluctuated over time. BCRABL1 overexpression, BCRABL1 kinase domain mutation, and overexpression of the small molecule transporter ABCG2, were identified as dasatinib resistance mechanisms. The acquisition of mutations followed an order corresponding with the increase in selective fitness associated with each resistance mechanism. Additionally, it was demonstrated that ABCG2 overexpression confers partial ponatinib resistance. The results of this study have broad applicability and help direct effective therapeutic drug usage and dosing regimens and may be useful for clinicians to select the most efficacious therapy at the most beneficial time.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Fusão bcr-abl
/
Inibidores de Proteínas Quinases
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Austrália