title: Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL.
abstract: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, tissue-resident CLL cells show prominent activation of both B-cell receptor (BCR) and NF-κB pathways. We evaluated the in vivo effects of ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor on tumor cell activation and proliferation in the blood, lymph node, and bone marrow of patients with CLL. Applying validated pathway-specific gene signatures, we detected a rapid and sustained downregulation of BCR and NF-κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment. Ibrutinib reduced phosphorylation of PLCγ2 and ERK and decreased nuclear protein expression of NF-κB p50. Ibrutinib significantly decreased tumor proliferation and expression of surface activation markers CD69 and CD86, independent of prognostic factors such as IGHV mutational status, chromosome 17p deletion, or prior treatment history. Interestingly, stronger inhibition of BCR signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2. Together, these data validate on-target effects of BTK inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo. This study is registered at www.clinicaltrials.gov as #NCT01500733.
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute and.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Herman
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute and.
authors.forename: Rashida Z
authors.initials: RZ
authors.lastname: Mustafa
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Gyamfi
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD; and.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Pharmacyclics Inc., Sunnyvale, CA.
authors.forename: Stella
authors.initials: S
authors.lastname: Chang
authors.affiliation: Pharmacyclics Inc., Sunnyvale, CA.
authors.forename: Betty
authors.initials: B
authors.lastname: Chang
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute and.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Farooqui
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute and.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000368:Aged; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000276:immunology*; D010880:Piperidines; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016328:NF-kappa B; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; C551803:ibrutinib; D000225:Adenine