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 Heinrich, Salah Mécheri, Thomas Tursz, Laurence Zitvogel

    Research output: Contribution to journalArticle

    232 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

    Fingerprint

    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.
    @article{a70b1327643441c492a259d1b3328218,
    title = "Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects",
    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.",
    author = "Christophe Borg and Magali Terme and Julien Ta{\"i}eb and C{\'e}dric M{\'e}nard and Caroline Flament and Caroline Robert and Koji Maruyama and Hiro Wakasugi and Eric Angevin and Kris Thielemans and {Le Cesne}, Axel and V{\'e}ronique Chung-Scott and Vladimir Lazar and Isabelle Tchou and Florent Cr{\'e}pineau and Fran{\cc}ois Lemoine and Jacky Bernard and Fletcher, {Jonhantan A.} and Ali Turhan and Blay, {Jean Yves} and Alain Spatz and Emile, {Jean Fran{\cc}ois} and Michael Heinrich and Salah M{\'e}cheri and Thomas Tursz and Laurence Zitvogel",
    year = "2004",
    month = "8",
    doi = "10.1172/JCI200421102",
    language = "English (US)",
    volume = "114",
    pages = "379--388",
    journal = "Journal of Clinical Investigation",
    issn = "0021-9738",
    publisher = "The American Society for Clinical Investigation",
    number = "3",

    }

    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

    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.

    UR - http://www.scopus.com/inward/record.url?scp=4043134677&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=4043134677&partnerID=8YFLogxK

    U2 - 10.1172/JCI200421102

    DO - 10.1172/JCI200421102

    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 -