BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Academic Article uri icon

Overview

MeSH

  • Cell Line, Tumor
  • Coculture Techniques
  • Humans
  • Prospective Studies

MeSH Major

  • Cell Proliferation
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Pyrazoles
  • Pyrimidines
  • Receptors, Antigen, B-Cell
  • Signal Transduction

abstract

  • Bruton agammaglobulinemia tyrosine kinase (BTK), a cytoplasmic protein tyrosine kinase, is a component of the B-cell receptor signaling pathway. Ibrutinib, a BTK inhibitor, has demonstrated a significant clinical activity against chronic lymphocytic leukemia (CLL) in early clinical trials. Understanding the molecular mechanisms of action would shed light on CLL pathophysiology and provide additional opportunities for the development of new therapies. In this study, we have chosen an in vivo approach by employing an ongoing phase 1b trial of ibrutinib. We prospectively collected and analyzed serial samples from the CLL patients before and after the initiation of ibrutinib. We found that the blockage of cell proliferation was one of the primary effects of ibrutinib against leukemic CLL cells in vivo. Using a co-culture system that induces CLL proliferation in vitro, analysis of several parameters, including Ki-67 expression and bromodeoxyuridine (BrdU) incorporation, revealed that the proliferation of CLL cells was directly inhibited by ibrutinib. Furthermore, activities of BTK and phospholipase Cγ2 as well as downstream signaling molecules, AKT and ERK, were all coordinately downregulated over time in ibrutinib-treated patients. Our findings suggest that the cell proliferation is one of the essential properties of CLL. Blocking cell proliferation via inhibition of BTK-mediated signaling may contribute to clinical responses in ibrutinib-treated patients.

publication date

  • March 2014

has subject area

  • Cell Line, Tumor
  • Cell Proliferation
  • Coculture Techniques
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Prospective Studies
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Pyrazoles
  • Pyrimidines
  • Receptors, Antigen, B-Cell
  • Signal Transduction

Research

keywords

  • Clinical Trial, Phase I
  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1038/leu.2013.358

PubMed ID

  • 24270740

Additional Document Info

start page

  • 649

end page

  • 657

volume

  • 28

number

  • 3