Novel mouse model resistant to irreversible BTK inhibitors: a tool identifying new therapeutic targets and side effects.
Blood Adv
; 4(11): 2439-2450, 2020 06 09.
Article
en En
| MEDLINE
| ID: mdl-32492159
ABSTRACT
Pharmacological inhibitors of Bruton tyrosine kinase (BTK) have revolutionized treatment of B-lymphocyte malignancies and show great promise for dampening autoimmunity. The predominant BTK inhibitors tether irreversibly by covalently binding to cysteine 481 in the BTK catalytic domain. Substitution of cysteine 481 for serine (C481S) is the most common mechanism for acquired drug resistance. We generated a novel C481S knock-in mouse model and, using a battery of tests, no overt B-lymphocyte phenotype was found. B lymphocytes from C481S animals were resistant to irreversible, but sensitive to reversible, BTK inhibitors. In contrast, irreversible inhibitors equally impaired T-lymphocyte activation in mice, mimicking the effect of treatment in patients. This demonstrates that T-lymphocyte blockage is independent of BTK. We suggest that the C481S knock-in mouse can serve as a useful tool for the study of BTK-independent effects of irreversible inhibitors, allowing for the identification of novel therapeutic targets and pinpointing potential side effects.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Linfocitos B
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Inhibidores de Proteínas Quinasas
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Agammaglobulinemia Tirosina Quinasa
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Blood Adv
Año:
2020
Tipo del documento:
Article
País de afiliación:
Suecia