Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects
| Autor: | Salah Mecheri, Jonhantan A. Fletcher, Kris Thielemans, Florent Crépineau, Jacky Bernard, Caroline Flament, Julien Taieb, Isabelle Tchou, Jean-Yves Blay, J.F. Emile, Cédric Ménard, Alain Spatz, Vladimir Lazar, Eric Angevin, Véronique Chung-Scott, Magali Terme, François M. Lemoine, Laurence Zitvogel, Christophe Borg, Hiro Wakasugi, Ali G. Turhan, Michael Heinrich, Thomas Tursz, Axel Le Cesne, Koji Maruyama, Caroline Robert |
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| Přispěvatelé: | Physiology |
| Jazyk: | angličtina |
| Rok vydání: | 2004 |
| Předmět: |
tumor
Antineoplastic Agents Mice SCID c-kit tyrosine kinase inhibitors Article Neutrophil Activation Piperazines Receptor tyrosine kinase Interferon-gamma Mice In vivo Animals Humans Receptors Platelet-Derived Growth Factor Longitudinal Studies Enzyme Inhibitors Mode of action Receptor Gastrointestinal Neoplasms Mice Knockout biology Receptor Protein-Tyrosine Kinases Dendritic Cells General Medicine Protein-Tyrosine Kinases Coculture Techniques Gene Expression Regulation Neoplastic Killer Cells Natural Mice Inbred C57BL Proto-Oncogene Proteins c-kit Pyrimidines Imatinib mesylate Case-Control Studies Benzamides Mutation Imatinib Mesylate Leukocytes Mononuclear Cancer research biology.protein Female Stromal Cells Tyrosine kinase Platelet-derived growth factor receptor |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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