Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765

• Published in: Blood Vol. 117; no. 23; pp. 6287 - 6296
• Main Authors: Herman, Sarah E.M., Gordon, Amber L., Hertlein, Erin, Ramanunni, Asha, Zhang, Xiaoli, Jaglowski, Samantha, Flynn, Joseph, Jones, Jeffrey, Blum, Kristie A., Buggy, Joseph J., Hamdy, Ahmed, Johnson, Amy J., Byrd, John C.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 09-06-2011; Americain Society of Hematology; American Society of Hematology
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Animals; Apoptosis - drug effects; Apoptosis - genetics; B-Cell Activating Factor - genetics; B-Cell Activating Factor - metabolism; B-Lymphocytes - enzymology; Biological and medical sciences; CD40 Ligand - genetics; CD40 Ligand - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - genetics; Drug Screening Assays, Antitumor - methods; Female; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - genetics; Gene Expression Regulation, Leukemic - drug effects; Gene Expression Regulation, Leukemic - genetics; Hematologic and hematopoietic diseases; Humans; Interleukin-4 - genetics; Interleukin-4 - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - enzymology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoid Neoplasia; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Medical sciences; Mice; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; NF-kappa B - genetics; NF-kappa B - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - biosynthesis; Protein-Tyrosine Kinases - genetics; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - metabolism; T-Lymphocytes - enzymology; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Chronic lymphocytic leukemia; Bruton tyrosine kinase; Treatment; Targeting; Hematology; Targeted therapy; Lymphoproliferative syndrome; Malignant hemopathy; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-01-328484

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.