Novel mouse model resistant to irreversible BTK inhibitors: a tool identifying new therapeutic targets and side effects

• Published in: Blood advances 2020-06, Vol.4 (11), p.2439-2450
• Main Authors: Estupiñán, H. Yesid, Bouderlique, Thibault, He, Chenfei, Berglöf, Anna, Gupta, Dhanu, Saher, Osama, Daza Cruz, Miguel Ángel, Peña-Perez, Lucia, Yu, Liang, Zain, Rula, Karlsson, Mikael C.I., Månsson, Robert, Smith, C. I. Edvard
• Format: Article
• Language: English
• Subjects: Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors; Animals; B-Lymphocytes; Humans; Lymphoid Neoplasia; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mutation; Protein Kinase Inhibitors - pharmacology
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2019001319

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. •BTK inhibitors revolutionized treatment; knock-in mice resistant to BTK inhibitors permit identification of new targets and side effects.•As proof of concept, we conclusively demonstrate that ibrutinib inhibits T cells irrespective of BTK. [Display omitted]