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BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib

Estupiñán, H. Yesid ; Wang, Qing ; Berglöf, Anna ; Schaafsma, Gerard C.P. LU orcid ; Shi, Yuye ; Zhou, Litao ; Mohammad, Dara K. ; Yu, Liang ; Vihinen, Mauno LU orcid and Zain, Rula , et al. (2021) In Leukemia 35(5). p.1317-1329
Abstract

Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the “gatekeeper” residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or... (More)

Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the “gatekeeper” residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Leukemia
volume
35
issue
5
pages
13 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:33526860
  • scopus:85100270165
ISSN
0887-6924
DOI
10.1038/s41375-021-01123-6
language
English
LU publication?
yes
id
08d0e19d-6a95-4322-9589-133eca9e4c86
date added to LUP
2021-02-15 10:30:28
date last changed
2024-06-27 08:31:31
@article{08d0e19d-6a95-4322-9589-133eca9e4c86,
  abstract     = {{<p>Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the “gatekeeper” residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.</p>}},
  author       = {{Estupiñán, H. Yesid and Wang, Qing and Berglöf, Anna and Schaafsma, Gerard C.P. and Shi, Yuye and Zhou, Litao and Mohammad, Dara K. and Yu, Liang and Vihinen, Mauno and Zain, Rula and Smith, C. I.Edvard}},
  issn         = {{0887-6924}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{5}},
  pages        = {{1317--1329}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Leukemia}},
  title        = {{BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib}},
  url          = {{http://dx.doi.org/10.1038/s41375-021-01123-6}},
  doi          = {{10.1038/s41375-021-01123-6}},
  volume       = {{35}},
  year         = {{2021}},
}