title: The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro.
abstract: Dasatinib (BMS-354825) is a Src/ABL tyrosine kinase inhibitor currently approved for the treatment of chronic myeloid leukemia. Dasatinib has increased potency against ABL compared to the current therapy imatinib, and is effective in many cases where disease is resistant to imatinib. Dasatinib also inhibits many Src-family tyrosine kinases. We have demonstrated in this study that dasatinib is able to block the function of normal human T-lymphocytes in vitro at clinically relevant concentrations. T-cell functions including proliferation, activation and cytokine production were all uniformly inhibited in the presence of dasatinib. We also demonstrated inhibition of TCR signalling through Src-family kinase LCK, and predicted that inhibition of LCK and other kinases involved in T-cell signalling by dasatinib is responsible for the suppression of T-cell function. These findings raise the concern about potential T-cell inhibition in patients taking dasatinib, and suggest a possible application for the treatment of T-cell mediated immune disorders.
authors.affiliation: Hanson Institute for Cancer Research, IMVS Adelaide, Australia. stephen.blake@imvs.sa.gov.au
authors.forename: Stephen
authors.initials: S
authors.lastname: Blake
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.forename: Graham
authors.initials: G
authors.lastname: Mayrhofer
authors.forename: A Bruce
authors.initials: AB
authors.lastname: Lyons
mesh_terms: D015703:Antigens, CD / Q000032:analysis / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis / Q000276:immunology; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D016374:Oncogene Proteins v-abl / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000069439:Dasatinib; D007371:Interferon-gamma; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D016374:Oncogene Proteins v-abl; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; D013844:Thiazoles; D019061:src-Family Kinases; D000099192:CD69 Antigens