Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.

Date publication

août 2004

Journal

The Journal of clinical investigation

Auteurs

Membres identifiés du Cancéropôle Est :
Pr BORG Christophe

Tous les auteurs :
Borg C, Terme M, Taïeb J, Ménard C, Flament C, Robert C, Maruyama K, Wakasugi H, Angevin E, Thielemans K, Le Cesne A, Chung-Scott V, Lazar V, Tchou I, Crépineau F, Lemoine F, Bernard J, Fletcher JA, Turhan A, Blay JY, Spatz A, Emile JF, Heinrich MC, Mécheri S, Tursz T, Zitvogel L

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/15286804

Résumé

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.

Mots clés

Animals, Antineoplastic Agents, pharmacology, Benzamides, Case-Control Studies, Coculture Techniques, Dendritic Cells, drug effects, Enzyme Inhibitors, pharmacology, Female, Gastrointestinal Neoplasms, drug therapy, Gene Expression Regulation, Neoplastic, Humans, Imatinib Mesylate, Interferon-gamma, drug effects, Killer Cells, Natural, metabolism, Leukocytes, Mononuclear, metabolism, Longitudinal Studies, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, SCID, Mutation, Neutrophil Activation, drug effects, Piperazines, pharmacology, Protein-Tyrosine Kinases, antagonists & inhibitors, Proto-Oncogene Proteins c-kit, drug effects, Pyrimidines, pharmacology, Receptor Protein-Tyrosine Kinases, drug effects, Receptors, Platelet-Derived Growth Factor, drug effects, Stromal Cells, drug effects

Référence

J. Clin. Invest.. 2004 Aug;114(3):379-88