The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia.

Abstract

Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton tyrosine kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin α(4)β(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLL cells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.

• Authors: Martin F M de Rooij, Annemieke Kuil, Christian R Geest, Eric Eldering, Betty Y Chang, Joseph J Buggy, Steven T Pals, Marcel Spaargaren
• Journal: Blood (Blood) Vol. 119 Issue 11 Pg. 2590-4 (Mar 15 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22279054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines
• Fibronectins
• Integrin alpha4beta1
• Piperidines
• Pyrazoles
• Pyrimidines
• RNA, Messenger
• Receptors, Antigen, B-Cell
• Vascular Cell Adhesion Molecule-1
• ibrutinib
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• BTK protein, human
• Adenine

Topics

• Adenine (analogs & derivatives)
• Agammaglobulinaemia Tyrosine Kinase
• Apoptosis (drug effects)
• Blotting, Western
• Cell Adhesion (drug effects)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Chemokines (metabolism)
• Fibronectins (metabolism)
• Flow Cytometry
• Humans
• Integrin alpha4beta1 (metabolism)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, metabolism, pathology)
• Piperidines
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• RNA, Messenger (genetics)
• Receptors, Antigen, B-Cell (metabolism)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• Vascular Cell Adhesion Molecule-1 (metabolism)