TY - JOUR
T1 - Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects
AU - Borg, Christophe
AU - Terme, Magali
AU - Taïeb, Julien
AU - Ménard, Cédric
AU - Flament, Caroline
AU - Robert, Caroline
AU - Maruyama, Koji
AU - Wakasugi, Hiro
AU - Angevin, Eric
AU - Thielemans, Kris
AU - Le Cesne, Axel
AU - Chung-Scott, Véronique
AU - Lazar, Vladimir
AU - Tchou, Isabelle
AU - Crépineau, Florent
AU - Lemoine, François
AU - Bernard, Jacky
AU - Fletcher, Jonhantan A.
AU - Turhan, Ali
AU - Blay, Jean Yves
AU - Spatz, Alain
AU - Emile, Jean François
AU - Heinrich, Michael C.
AU - Mécheri, Salah
AU - Tursz, Thomas
AU - Zitvogel, Laurence
PY - 2004/8
Y1 - 2004/8
N2 - 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-γ production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.
AB - 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-γ production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.
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U2 - 10.1172/JCI21102
DO - 10.1172/JCI21102
M3 - Article
C2 - 15286804
AN - SCOPUS:4043134677
VL - 114
SP - 379
EP - 388
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 3
ER -