title: The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo.
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.
authors.affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77230, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Ponader
authors.forename: Shih-Shih
authors.initials: SS
authors.lastname: Chen
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Buggy
authors.forename: Kumudha
authors.initials: K
authors.lastname: Balakrishnan
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology*; D017254:Leukemic Infiltration / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D000225:Adenine