1. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia.
- Author
-
de Rooij, Martin F. M., Kuil, Annemieke, Geest, Christian R., Eidering, Eric, Chang, Betty Y., Buggy, Joseph J., Pals, Steven T., and Spaargaren, Marcel
- Subjects
- *
PROTEIN-tyrosine kinase inhibitors , *CELL receptors , *CHEMOKINES , *LYMPHOCYTIC leukemia , *B cells , *CELL lines , *PATIENTS - Abstract
Small-molecule drugs that target the B-cell antigen receptor (BCR) signalo-some 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 tran sient 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 &agr;4&bgr;1mediated 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 [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF