4.7 Article

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

Journal

LEUKEMIA
Volume 35, Issue 5, Pages 1317-1329

Publisher

SPRINGERNATURE
DOI: 10.1038/s41375-021-01123-6

Keywords

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Funding

  1. CIES grants from the Swedish Cancer Society
  2. Swedish County Council (ALF-project)
  3. CIES
  4. Swedish Medical Research Council
  5. Research Council
  6. Swedish Cancer Society
  7. COLCIENCIAS-Minciencias Colombia [756]
  8. Science and Technology Fund of Jiangsu Commission of Health [H2018085]
  9. 333 Projects Foundation of Jiangsu Province [BRA2017243]
  10. 533 Projects Foundation of Huai'an City [HAA201739]

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Certain double mutants were found to be super-resistant to irreversible inhibitors, while reversible inhibitors showed variable patterns from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors that may affect their clinical application.
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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