2. Academic Validation
  3. Novel mouse model resistant to irreversible BTK inhibitors: a tool identifying new therapeutic targets and side effects

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

  • Blood Adv. 2020 Jun 9;4(11):2439-2450. doi: 10.1182/bloodadvances.2019001319.
H Yesid Estupiñán 1 2,  Thibault Bouderlique 3,  Chenfei He 4,  Anna Berglöf 1,  Dhanu Gupta 1,  Osama Saher 1 5,  Miguel Ángel Daza Cruz 1 2,  Lucia Peña-Perez 3,  Liang Yu 6,  Rula Zain 1 7,  Mikael C I Karlsson 4,  Robert Månsson 3 8,  C I Edvard Smith 1
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
  • 2 Departamento de Ciencias Básicas, Universidad Industrial de Santander, Bucaramanga, Colombia.
  • 3 Department of Laboratory Medicine, Center for Hematology and Regenerative Medicine, and.
  • 4 Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
  • 5 Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
  • 6 Department of Hematology, Huai'an First People's Hospital, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China; and.
  • 7 Centre for Rare Diseases, Department of Clinical Genetics, and.
  • 8 Hematology Center, Karolinska University Hospital, Stockholm, Sweden.
PMID: 32492159 DOI: 10.1182/bloodadvances.2019001319
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.

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