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 Blay & 6 others Alain Spatz, Jean François Emile, Michael Heinrich, Salah Mécheri, Thomas Tursz, Laurence Zitvogel

    Research output: Contribution to journalArticle

    231 Citations (Scopus)

    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

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    Natural Killer Cells
    Protein-Tyrosine Kinases
    Gastrointestinal Stromal Tumors
    Imatinib Mesylate
    Platelet-Derived Growth Factor Receptors
    Mutation
    Receptor Protein-Tyrosine Kinases
    Longitudinal Studies
    Protein Isoforms
    Therapeutics

    ASJC Scopus subject areas

    • Medicine(all)

    Cite this

    Borg, C., Terme, M., Taïeb, J., Ménard, C., Flament, C., Robert, C., ... Zitvogel, L. (2004). Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. Journal of Clinical Investigation, 114(3), 379-388. https://doi.org/10.1172/JCI200421102

    Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. / Borg, Christophe; Terme, Magali; Taïeb, Julien; Ménard, Cédric; Flament, Caroline; Robert, Caroline; Maruyama, Koji; Wakasugi, Hiro; Angevin, Eric; Thielemans, Kris; Le Cesne, Axel; Chung-Scott, Véronique; Lazar, Vladimir; Tchou, Isabelle; Crépineau, Florent; Lemoine, François; Bernard, Jacky; Fletcher, Jonhantan A.; Turhan, Ali; Blay, Jean Yves; Spatz, Alain; Emile, Jean François; Heinrich, Michael; Mécheri, Salah; Tursz, Thomas; Zitvogel, Laurence.

    In: Journal of Clinical Investigation, Vol. 114, No. 3, 08.2004, p. 379-388.

    Research output: Contribution to journalArticle

    Borg, C, Terme, M, Taïeb, J, Ménard, C, Flament, C, Robert, C, Maruyama, K, Wakasugi, H, Angevin, E, Thielemans, K, Le Cesne, A, Chung-Scott, V, Lazar, V, Tchou, I, Crépineau, F, Lemoine, F, Bernard, J, Fletcher, JA, Turhan, A, Blay, JY, Spatz, A, Emile, JF, Heinrich, M, Mécheri, S, Tursz, T & Zitvogel, L 2004, 'Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects', Journal of Clinical Investigation, vol. 114, no. 3, pp. 379-388. https://doi.org/10.1172/JCI200421102
    Borg, Christophe ; Terme, Magali ; Taïeb, Julien ; Ménard, Cédric ; Flament, Caroline ; Robert, Caroline ; Maruyama, Koji ; Wakasugi, Hiro ; Angevin, Eric ; Thielemans, Kris ; Le Cesne, Axel ; Chung-Scott, Véronique ; Lazar, Vladimir ; Tchou, Isabelle ; Crépineau, Florent ; Lemoine, François ; Bernard, Jacky ; Fletcher, Jonhantan A. ; Turhan, Ali ; Blay, Jean Yves ; Spatz, Alain ; Emile, Jean François ; Heinrich, Michael ; Mécheri, Salah ; Tursz, Thomas ; Zitvogel, Laurence. / Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. In: Journal of Clinical Investigation. 2004 ; Vol. 114, No. 3. pp. 379-388.
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    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.",
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    AU - Blay, Jean Yves

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    AU - Emile, Jean François

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