title: Gefitinib targets ZAP-70-expressing chronic lymphocytic leukemia cells and inhibits B-cell receptor signaling.
abstract: Chronic lymphocytic leukemia (CLL) can be divided into groups based on biomarkers of poor prognosis. The expression of the tyrosine kinase ZAP-70 (member of the Syk tyrosine kinase family) in CLL cells is associated with shorter overall survival in CLL patients. Currently, there is a lack of targeted therapies for patients with ZAP-70 expression in CLL cells. The tyrosine kinase inhibitor gefitinib has been shown to be effective at induce apoptosis in acute myeloid leukemia through inhibition of Syk. In this study, we sought to test the efficacy of gefitinib in primary human ZAP-70+ CLL cells. We demonstrate that gefitinib preferentially induces cell death in ZAP-70-expressing CLL cells with a median IC50 of 4.5 μM. In addition, gefitinib decreases the viability of ZAP-70+ Jurkat T leukemia cells but fails to affect T cells from CLL patients. Western blot analysis shows gefitinib reduces both basal and B-cell receptor (BCR)-stimulated phosphorylation of Syk/ZAP-70, ERK, and Akt in ZAP-70+ CLL cells. Moreover, gefitinib inhibits the pro-survival response from BCR stimulation and decreases pro-survival proteins such as Mcl-1. Finally, ZAP-70 expression sensitizes Raji cells to gefitinib treatment. These results demonstrate that gefitinib specifically targets ZAP-70+ CLL cells and inhibits the BCR cell survival pathway leading to apoptosis. This represents the likelihood of tyrosine kinase inhibitors being effective targeted treatments for ZAP-70+ CLL cells.
authors.affiliation: 1] Department of Immunology, University of Manitoba, Winnipeg, MB, Canada [2] Manitoba Institute of Cell Biology, Winnipeg, MB, Canada.
authors.forename: R F
authors.initials: RF
authors.lastname: Dielschneider
authors.affiliation: Manitoba Institute of Cell Biology, Winnipeg, MB, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Xiao
authors.affiliation: 1] Manitoba Institute of Cell Biology, Winnipeg, MB, Canada [2] Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Yoon
authors.affiliation: Manitoba Institute of Cell Biology, Winnipeg, MB, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Noh
authors.affiliation: 1] Manitoba Institute of Cell Biology, Winnipeg, MB, Canada [2] Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada [3] Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Banerji
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: A J
authors.initials: AJ
authors.lastname: Marshall
authors.affiliation: 1] Manitoba Institute of Cell Biology, Winnipeg, MB, Canada [2] Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: J B
authors.initials: JB
authors.lastname: Johnston
authors.affiliation: 1] Department of Immunology, University of Manitoba, Winnipeg, MB, Canada [2] Manitoba Institute of Cell Biology, Winnipeg, MB, Canada [3] Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada [4] Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: S B
authors.initials: SB
authors.lastname: Gibson
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D000077156:Gefitinib; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011947:Receptors, Antigen, B-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D000077156:Gefitinib