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Cited by 640Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo

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Ponader, Sabine, Chen, Shih-Shih, Buggy, Joseph J., Balakrishnan, Kumudha, Gandhi, Varsha, Wierda, William G., Keating, Michael J., O'Brien, Susan +2 more·2012·Blood
DOI 10.1182/blood-2011-10-386417PMC PMC4916557
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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.

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  • Ibrutinib is an irreversible inhibitor of BTK.

    “Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL).”

    From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [8]

    The Introduction states that PCI-32765 binds irreversibly to BTK, supporting the inhibitor property. Our copy does not identify PCI-32765 as ibrutinib, so it does not establish that the named drug has that property. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Ibrutinib irreversibly binds BTK at the C481 residue.

    “Ibrutinib irreversibly binds BTK at the C481 residue, rendering it kinase-inactive”

    From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [8]

    The Introduction (page not provided) says PCI-32765 binds irreversibly to a cysteine residue in BTK and inhibits its enzymatic activity. It does not identify that residue as C481; a search for “C481” found no matching passage. The copy calls the drug PCI-32765 rather than ibrutinib. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Authors
Ponader, S., Chen, S.-S., Buggy, J. J., Balakrishnan, K., Gandhi, V., Wierda, W. G., Keating, M. J., O'Brien, S., Chiorazzi, N., & Burger, J. A.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Feinstein Institute for Medical Research (US)
  • Pharmacyclics (United States) (US)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2012-02-02
Volume
119
Issue
5
Pages
1182-1189
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2011-10-386417
PMC
PMC4916557
OpenAlex
W2011950935
Cited by
640
References
0
Citations by year
2026: 5 · 2025: 17 · 2024: 22 · 2023: 22 · 2022: 33 · 2021: 42 · 2020: 56 · 2019: 49 · 2018: 44 · 2017: 58 · 2016: 53 · 2015: 73 · 2014: 66 · 2013: 68 · 2012: 30
FWCI
26.62
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Cancer Prevention and Research Institute of Texas
  • CLL Global Research Foundation
  • Pharmacyclics
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
Keywords
BTK inhibitors, chronic lymphocytic leukemia, B cell receptor signaling, CLL cell survival, cell migration, tissue homing, CXCL12, CXCL13, CCL3, carbon tetrachloride, chemokine secretion, targeted therapy
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Adenine, Animals, Antineoplastic Agents, Cell Survival, Cells, Cultured, Chemotaxis, Leukocyte, Humans, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, Mice, SCID, Leukemic Infiltration, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors, Mice

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