title: Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.
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.
authors.affiliation: Integrated Biomedical Science Graduate Program, The Ohio State University Medical Center, Columbus, OH, USA.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Herman
authors.forename: Amber L
authors.initials: AL
authors.lastname: Gordon
authors.forename: Erin
authors.initials: E
authors.lastname: Hertlein
authors.forename: Asha
authors.initials: A
authors.lastname: Ramanunni
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Samantha
authors.initials: S
authors.lastname: Jaglowski
authors.forename: Joseph
authors.initials: J
authors.lastname: Flynn
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Buggy
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hamdy
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000201:enzymology; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000225:Adenine; D000077329:Agammaglobulinaemia Tyrosine Kinase; D053264:B-Cell Activating Factor; D023201:CD40 Ligand; D015847:Interleukin-4; D015850:Interleukin-6; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D010880:Piperidines; D011505:Protein-Tyrosine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; D014409:Tumor Necrosis Factor-alpha; C508598:IL4 protein, human; C508600:IL6 protein, human; C505719:TNFSF13B protein, human; C551803:ibrutinib; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C535150:MAPK1 protein, human