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

Christophe Borg, Magali Terme, Julien Taïeb, Cédric Ménard, Caroline Flament, Caroline Robert, Koji Maruyama, Hiro Wakasugi, Eric Angevin, Kris Thielemans, Axel Le Cesne, Véronique Chung-Scott, Vladimir Lazar, Isabelle Tchou, Florent Crépineau, François Lemoine, Jacky Bernard, Jonhantan A. Fletcher, Ali Turhan, Jean Yves BlayAlain Spatz, Jean François Emile, Michael C. Heinrich, Salah Mécheri, Thomas Tursz, Laurence Zitvogel

    Research output: Contribution to journalArticlepeer-review

    239 Scopus citations

    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-γ production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.

    Original languageEnglish (US)
    Pages (from-to)379-388
    Number of pages10
    JournalJournal of Clinical Investigation
    Volume114
    Issue number3
    DOIs
    StatePublished - Aug 2004

    ASJC Scopus subject areas

    • Medicine(all)

    Fingerprint Dive into the research topics of 'Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects'. Together they form a unique fingerprint.

    Cite this