Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors

S Cheng; A Guo; P Lu; J Ma; M Coleman; Y L Wang

doi:10.1038/leu.2014.263

Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors

Leukemia. 2015 Apr;29(4):895-900. doi: 10.1038/leu.2014.263. Epub 2014 Sep 5.

Authors

S Cheng¹, A Guo², P Lu², J Ma¹, M Coleman³, Y L Wang²

Affiliations

¹ Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
² Department of Pathology, University of Chicago, Chicago, IL, USA.
³ Department of Medicine, Weill Cornell Medical College, New York, NY, USA.

PMID: 25189416
DOI: 10.1038/leu.2014.263

Abstract

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 types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adenine / analogs & derivatives
Agammaglobulinaemia Tyrosine Kinase
Antineoplastic Agents / pharmacology*
B-Lymphocytes / drug effects
B-Lymphocytes / metabolism
B-Lymphocytes / pathology
Cell Line, Tumor
Cyclohexylamines / pharmacology
Dasatinib
Drug Resistance, Neoplasm
Female
Gene Expression
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
Leukemia, Lymphocytic, Chronic, B-Cell / enzymology
Leukemia, Lymphocytic, Chronic, B-Cell / genetics
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
Middle Aged
Mutation
Piperidines / pharmacology
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / chemistry
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism
Pyrazoles / pharmacology*
Pyrimidines / pharmacology*
Pyrroles / pharmacology
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Structure-Activity Relationship
Thiazoles / pharmacology

Substances

2-(2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide
Antineoplastic Agents
Cyclohexylamines
Piperidines
Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
Pyrroles
RNA, Small Interfering
Thiazoles
ibrutinib
tofacitinib
Protein-Tyrosine Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human
Adenine
Dasatinib