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The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro

Stephen Blake1, Timothy P Hughes, Graham Mayrhofer

  • 1Hanson Institute for Cancer Research, IMVS Adelaide, Australia. stephen.blake@imvs.sa.gov.au

Clinical Immunology (Orlando, Fla.)
|April 9, 2008
PubMed

Insights

Dasatinib, a leukemia drug, inhibits normal human T-lymphocyte functions like proliferation and cytokine production. This T-cell inhibition, via Src-family kinase LCK, suggests potential side effects and therapeutic uses for immune disorders.

Area of Science:

  • Immunology
  • Pharmacology
  • Oncology

Background:

  • Dasatinib is a potent Src/ABL tyrosine kinase inhibitor used for chronic myeloid leukemia.
  • It shows higher efficacy than imatinib, particularly in resistant cases.
  • Dasatinib also targets Src-family tyrosine kinases.

Purpose of the Study:

  • To investigate the effect of dasatinib on normal human T-lymphocyte function in vitro.
  • To elucidate the mechanism of T-cell inhibition by dasatinib.
  • To explore potential clinical implications of dasatinib's T-cell effects.

Main Methods:

  • In vitro studies using normal human T-lymphocytes.
  • Assays to measure T-cell proliferation, activation, and cytokine production.
  • Analysis of T-cell receptor (TCR) signaling pathways, focusing on Src-family kinase LCK.

Main Results:

  • Dasatinib uniformly inhibited T-cell proliferation, activation, and cytokine production at clinically relevant concentrations.
  • Inhibition of TCR signaling was observed, specifically through the Src-family kinase LCK.
  • These effects are attributed to dasatinib's inhibition of LCK and other T-cell signaling kinases.

Conclusions:

  • Dasatinib suppresses normal human T-cell function in vitro.
  • Potential for T-cell mediated side effects in patients treated with dasatinib.
  • Suggests a potential therapeutic application of dasatinib in T-cell mediated immune disorders.

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