Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.
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.
Department of Clinical Biology, Equipe de Recherche Mixte 0208, INSERM, Institut Gustave Roussy, Villejuif, France.
Christophe
C
Borg
Magali
M
Terme
Julien
J
Taïeb
Cédric
C
Ménard
Caroline
C
Flament
Caroline
C
Robert
Koji
K
Maruyama
Hiro
H
Wakasugi
Eric
E
Angevin
Kris
K
Thielemans
Axel
A
Le Cesne
Véronique
V
Chung-Scott
Vladimir
V
Lazar
Isabelle
I
Tchou
Florent
F
Crépineau
François
F
Lemoine
Jacky
J
Bernard
Jonhantan A
JA
Fletcher
Ali
A
Turhan
Jean-Yves
JY
Blay
Alain
A
Spatz
Jean-François
JF
Emile
Michael C
MC
Heinrich
Salah
S
Mécheri
Thomas
T
Tursz
Laurence
L
Zitvogel
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D016022:Case-Control Studies; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008137:Longitudinal Studies; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009154:Mutation; D018375:Neutrophil Activation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D007371:Interferon-gamma; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor