Functional characterization of BTK C481S mutation that confers ibrutinib resistance: Exploration of alternative kinase inhibitors Academic Article uri icon


MeSH Major

  • Antineoplastic Agents
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Pyrazoles
  • Pyrimidines


  • The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has produced remarkable clinical response in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. We previously reported the identification of BTK(C481S) mutation in a CLL patient who progressed following 21-month ibrutinib therapy. Initial characterization at structural and biochemical levels revealed that the mutation disrupts the covalent binding of ibrutinib to BTK, reduces its binding affinity and diminishes its ability to inhibit the BTK enzymatic activity. Herein, we further characterized the functional consequences of BTK(C481S) in terms of molecular signaling, gene expression and cellular behavior in the patient, as well as in lymphoma cells transfected with either the wild-type or the mutant BTK constructs. Further, using an in vitro CLL proliferation model, alternative kinase inhibitors that have the potential to overcome ibrutinib resistance were explored.

publication date

  • January 2015



  • Academic Article



  • eng

Digital Object Identifier (DOI)

  • 10.1038/leu.2014.263

PubMed ID

  • 25189416

Additional Document Info

start page

  • 895

end page

  • 900


  • 29


  • 4