Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell–dependent antitumor effects
Christophe Borg, … , Thomas Tursz, Laurence Zitvogel
Christophe Borg, … , Thomas Tursz, Laurence Zitvogel
Published August 1, 2004
Citation Information: J Clin Invest. 2004;114(3):379-388. https://doi.org/10.1172/JCI21102.
View: Text | PDF
Article Oncology

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

  • Text
  • PDF
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.

Authors

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, Alain Spatz, Jean-François Emile, Michael C. Heinrich, Salah Mécheri, Thomas Tursz, Laurence Zitvogel

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Gleevec prevented tumor progression in vivo in tumor models resistant to...
Gleevec prevented tumor progression in vivo in tumor models resistant to the Gleevec antiproliferative effects in vitro. (A) Mouse tumor models resistant to Gleevec in vitro. AK7, B16F10 (B16), RMA-S, MCA 102, or BAF3p210 cells (bearing the BCR/ABL translocation) were incubated for 24 hours with the indicated doses of Gleevec, and the absolute number of surviving cells was determined by trypan blue exclusion assay. Proliferation indexes are shown. The Wilcoxon two-sample rank sum test was used to compare the proliferation indexes (*P < 0.05). (B) Gleevec prevents establishment of B16F10 lung metastases. We injected 5 × 105 B16F10 tumor cells in the tail vein at day 0. Oral feeding with Gleevec (150 mg/kg bid) or H2O (200 μl) was administered on days 5–11 and mice were sacrificed for the enumeration of lung metastases on day 11. The data from 3 independent experiments, each including 5–7 mice per group, were pooled and are depicted. The Wilcoxon two-sample rank sum test was used to compare the number of lung metastases (**P < 0.05, Gleevec versus H2O). (C) FL and Gleevec synergize to eradicate AK7. We inoculated 3 × 106 AK7 tumor cells in the abdominal flank of C57BL/6 mice on day 0. FL was started at day 11 when AK7 tumors reached a diameter of 20 ± 20 mm2. FL was continued for 10 days and combined with Gleevec the day before FL arrest and for 8 consecutive days (same doses as in B). Each experiment included 5–7 mice/group and was repeated twice with similar results. The Kruskal Wallis multiple comparison test was used for statistical analyses and significant effects are signified by triple asterisks.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts