Functional characterization of BTK.sup.C481S mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors

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.sup.C481S mutation in a CLL patient who progressed following 21-month ibrutinib therapy. I...

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Bibliographic Details
Published inLeukemia Vol. 29; no. 4; p. 895
Main Authors Lu, P, Cheng, S, Ma, J, Coleman, M, Wang, Y L, Guo, A
Format Journal Article
LanguageEnglish
Published Nature Publishing Group 01.04.2015
Subjects
Chronic lymphocytic leukemia
Development and progression
Drug resistance
Drug therapy
Gene mutations
Genetic aspects
Health aspects
United States
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Summary: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.sup.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.sup.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.
ISSN:0887-6924