Cell-Intrinsic Determinants of Ibrutinib-Induced Apoptosis in Chronic Lymphocytic Leukemia

Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, is approved for the treatment of relapsed chronic lymphocytic leukemia (CLL) and CLL with del17p. Mechanistically, ibrutinib interferes with B-cell receptor (BCR) signaling as well as multiple CLL cell-to-microenvironment interactions. Given the i...

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Bibliographic Details
Published in:Clinical cancer research 2017-02, Vol.23 (4), p.1049-1059
Main Authors: Amin, Nisar A, Balasubramanian, Sriram, Saiya-Cork, Kamlai, Shedden, Kerby, Hu, Nan, Malek, Sami N
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - drug effects
B-cell receptor
Biomarkers, Pharmacological
Bruton's tyrosine kinase
Cancer
Chemotherapy
Chronic lymphocytic leukemia
Drug Resistance, Neoplasm - genetics
Enzyme inhibitors
Experimental design
Female
Humans
Immunoblotting
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Lymphatic leukemia
Lymphocytes B
Male
Mutation
p53 Protein
Polymorphism, Single Nucleotide
Protein-tyrosine kinase
Pyrazoles - administration & dosage
Pyrazoles - adverse effects
Pyrimidines - administration & dosage
Pyrimidines - adverse effects
Resistance factors
Sensitivity
Signaling
Trisomy
Tumor Suppressor Protein p53 - genetics
Tyrosine
Whole Exome Sequencing
ZAP-70 protein
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Summary:Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, is approved for the treatment of relapsed chronic lymphocytic leukemia (CLL) and CLL with del17p. Mechanistically, ibrutinib interferes with B-cell receptor (BCR) signaling as well as multiple CLL cell-to-microenvironment interactions. Given the importance of ibrutinib in the management of CLL, a deeper understanding of factors governing sensitivity and resistance is warranted. We studied 48 longitudinally sampled paired CLL samples, 42 of which were procured before and after standard CLL chemotherapies, and characterized them for well-studied CLL molecular traits as well as by whole-exome sequencing and SNP 6.0 array profiling. We exposed these samples to 0.25 to 5 μmol/L of ibrutinib and measured apoptosis fractions as well as BCR signaling by immunoblotting. We disrupted in HG3, PGA1, and PG-EBV cell lines and measured BCR signaling and ibrutinib responses. CLL samples demonstrated a surprisingly wide range of sensitivities to ibrutinib, with IC values ranging from 0.4 to 9.7 μmol/L. Unmutated IGVH status, elevated ZAP70 expression, and trisomy 12 were associated with heightened sensitivity to ibrutinib treatment. Five CLL samples were substantially more resistant to ibrutinib following relapse from chemotherapy; of these, three had acquired a del17p/ -mutated status. A validation sample of 15 CLL carrying mutations, of which 13 carried both del17p and a mutation, confirmed substantially less sensitivity to ibrutinib-induced apoptosis. This study identifies that CLL harboring del17p/ -mutated cells are substantially less sensitive to ibrutinib-induced apoptosis than del17p/ wild-type cells. .
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-15-2921