Faculty Collaboration Database

Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 2011 Jun 09;117(23):6287-96

Date

03/23/2011

Pubmed ID

21422473

Pubmed Central ID

PMC3122947

DOI

10.1182/blood-2011-01-328484

Scopus ID

2-s2.0-79959404661 (requires institutional sign-in at Scopus site)   664 Citations

Abstract

B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell-specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted.

Author List

Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, Flynn J, Jones J, Blum KA, Buggy JJ, Hamdy A, Johnson AJ, Byrd JC

Author

Samantha M. Jaglowski MD, MPH Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenine
Animals
Apoptosis
B-Cell Activating Factor
B-Lymphocytes
CD40 Ligand
Cell Line, Tumor
Cell Proliferation
Cell Survival
Drug Screening Assays, Antitumor
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Leukemic
Humans
Interleukin-4
Interleukin-6
Leukemia, Lymphocytic, Chronic, B-Cell
MAP Kinase Signaling System
Male
Mice
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
NF-kappa B
Neoplasm Proteins
Phosphatidylinositol 3-Kinases
Piperidines
Protein-Tyrosine Kinases
Pyrazoles
Pyrimidines
Receptors, Antigen, B-Cell
T-Lymphocytes
Tumor Necrosis Factor-alpha