Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Benzamides
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Case-Control Studies
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Coculture Techniques
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Dendritic Cells / drug effects
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Dendritic Cells / metabolism
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Enzyme Inhibitors / pharmacology*
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Female
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Gastrointestinal Neoplasms / drug therapy
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Gastrointestinal Neoplasms / genetics
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Gastrointestinal Neoplasms / metabolism
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Gastrointestinal Neoplasms / pathology
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Gene Expression Regulation, Neoplastic
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Humans
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Imatinib Mesylate
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Interferon-gamma / drug effects
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Interferon-gamma / metabolism
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Killer Cells, Natural / metabolism*
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Leukocytes, Mononuclear / metabolism
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Longitudinal Studies
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, SCID
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Mutation
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Neutrophil Activation / drug effects
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Piperazines / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Proto-Oncogene Proteins c-kit / drug effects
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Proto-Oncogene Proteins c-kit / genetics*
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Proto-Oncogene Proteins c-kit / metabolism*
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Pyrimidines / pharmacology
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Receptor Protein-Tyrosine Kinases / drug effects
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptors, Platelet-Derived Growth Factor / drug effects
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Receptors, Platelet-Derived Growth Factor / genetics
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Receptors, Platelet-Derived Growth Factor / metabolism
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Stromal Cells / drug effects
Substances
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Antineoplastic Agents
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Benzamides
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Enzyme Inhibitors
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Piperazines
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Pyrimidines
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Interferon-gamma
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Imatinib Mesylate
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-kit
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Receptor Protein-Tyrosine Kinases
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Receptors, Platelet-Derived Growth Factor