The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo
Open Access
- 2 February 2012
- journal article
- Published by American Society of Hematology in Blood
- Vol. 119 (5), 1182-1189
- https://doi.org/10.1182/blood-2011-10-386417
Abstract
B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.Keywords
This publication has 40 references indexed in Scilit:
- Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765Blood, 2011
- CCL3 (MIP-1α) plasma levels and the risk for disease progression in chronic lymphocytic leukemiaBlood, 2011
- The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemiaBlood, 2011
- The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancyProceedings of the National Academy of Sciences of the United States of America, 2010
- Chronic active B-cell-receptor signalling in diffuse large B-cell lymphomaNature, 2010
- B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406Blood, 2009
- Primary B Cell Immunodeficiencies: Comparisons and ContrastsAnnual Review of Immunology, 2009
- The B Cell Antigen Receptor Controls Integrin Activity through Btk and PLCγ2The Journal of Experimental Medicine, 2003
- Bruton's Tyrosine Kinase Is Required for Activation of Iκb Kinase and Nuclear Factor κb in Response to B Cell Receptor EngagementThe Journal of Experimental Medicine, 2000
- Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemiaCell, 1993