Activities of SYK and PLCgamma2 predict apoptotic response of CLL cells to SRC tyrosine kinase inhibitor dasatinib. Academic Article Article uri icon

Overview

MeSH

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents
  • Biomarkers, Pharmacological
  • Cell Death
  • Dasatinib
  • Enzyme Activation
  • Female
  • Humans
  • Male
  • Middle Aged
  • Prognosis
  • Protein Kinase Inhibitors
  • Syk Kinase
  • Tumor Cells, Cultured
  • src-Family Kinases

MeSH Major

  • Apoptosis
  • Intracellular Signaling Peptides and Proteins
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Phospholipase C gamma
  • Protein-Tyrosine Kinases
  • Pyrimidines
  • Thiazoles

abstract

  • B-cell receptor signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). However, blocking B-cell receptor signaling with dasatinib, an inhibitor of SRC kinase, produced variable results in preclinical and clinical studies. We aim to define the molecular mechanisms underlying the differential dasatinib sensitivity and to uncover more effective therapeutic targets in CLL. Fresh CLL B cells were treated with dasatinib, and cell viability was followed. The CLL cases were then divided into good and poor responders. The cellular response was correlated with the activities of B-cell receptor signaling molecules, as well as with molecular and cytogenetic prognostic factors. Among 50 CLL cases, dasatinib treatment reduced cell viability by 2% to 90%, with an average reduction of 47% on day 4 of culture. The drug induced CLL cell death through the intrinsic apoptotic pathway mediated by reactive oxygen species. Unexpectedly, phosphorylation of SRC family kinases was inhibited by dasatinib in good, as well as poor, responders. As opposed to SRC family kinases, activities of two downstream molecules, SYK and phospholipase Cgamma2, correlate well with the apoptotic response of CLL cells to dasatinib. Thus, SYK inhibition predicts cellular response to dasatinib. SYK, together with phospholipase Cgamma2, may serve as potential biomarkers to predict dasatinib therapeutic response in patients. From the pathogenic perspective, our study suggests the existence of alternative mechanisms or pathways that activate SYK, independent of SRC kinase activities. The study further implicates that SYK might serve as a more effective therapeutic target in CLL treatment.

publication date

  • January 15, 2010

has subject area

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents
  • Apoptosis
  • Biomarkers, Pharmacological
  • Cell Death
  • Dasatinib
  • Enzyme Activation
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Male
  • Middle Aged
  • Phospholipase C gamma
  • Prognosis
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Pyrimidines
  • Syk Kinase
  • Thiazoles
  • Tumor Cells, Cultured
  • src-Family Kinases

Research

keywords

  • Evaluation Studies
  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-09-1519

PubMed ID

  • 20068106

Additional Document Info

start page

  • 587

end page

  • 599

volume

  • 16

number

  • 2