Clinical & Experimental Metastasis

, Volume 31, Issue 5, pp 553–564 | Cite as

Mechanisms of resistance to imatinib mesylate in KIT-positive metastatic uveal melanoma

  • Armelle Calipel
  • Solange Landreville
  • Arnaud De La Fouchardière
  • Frédéric Mascarelli
  • Michel Rivoire
  • Nicolas Penel
  • Frédéric MouriauxEmail author
Research Paper


Imatinib mesylate is used in targeted therapy of cancer to inhibit type III tyrosine kinase receptors, such as KIT and platelet-derived growth factor receptors (PDGFRs). Expression of KIT in uveal melanoma (UM) suggests that this receptor may be the target of imatinib mesylate therapy. However, phase II multicenter clinical studies have shown no effect of imatinib mesylate in patients with unresectable liver metastases of UM. We therefore investigated which molecular mechanisms promote imatinib mesylate-resistance in metastatic UM. Expression of KIT, stem cell factor (SCF), PDGFRα and PDGFRβ, was analyzed by RT-PCR, immunostaining, and Western blot in twenty-four samples of UM liver metastases, as well as UM primary tumor and metastatic cell lines. Soluble SCF was quantified in UM cell lines using enzyme-linked immunosorbent assay. Cell viability of UM cell lines treated with imatinib mesylate and grown in SCF-supplemented medium or in microvascular endothelial cells-conditioned medium was studied by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assays. UM liver metastases and cell lines expressed KIT and SCF, but not the PDGFRs. Ninety-five percent of liver metastases expressed KIT at the protein level, but PDGFRs were not detected in these samples. Imatinib mesylate reduced the viability of UM metastatic cell lines in a concentration-dependent manner, but an increased resistance to this drug was observed when cells were incubated in SCF-supplemented or microvascular endothelial cells-conditioned medium. This study provides evidence that tumor microenvironment cytokines such as SCF may promote resistance to imatinib mesylate in metastatic UM.


Uveal melanoma Imatinib mesylate Metastasis KIT Stem cell factor Targeted therapy 



We thank Dr. Eduardo Angles-Cano and Loïc Doeuvre for providing the HMEC-conditioned medium. This study was supported by a Clinical Research Grant (RC-071-2005) from the Institute National du Cancer (Cancéro-pôle Nord-Ouest).

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Armelle Calipel
    • 1
    • 2
    • 3
  • Solange Landreville
    • 4
    • 5
  • Arnaud De La Fouchardière
    • 6
  • Frédéric Mascarelli
    • 7
    • 8
    • 9
  • Michel Rivoire
    • 6
  • Nicolas Penel
    • 10
  • Frédéric Mouriaux
    • 1
    • 2
    • 3
    • 4
    • 5
    • 11
    Email author
  1. 1.CNRSCaenFrance
  2. 2.CEACaenFrance
  3. 3.Université de Caen Basse-NormandieCaenFrance
  4. 4.Centre universitaire d’ophtalmologie-Recherche, Hôpital du Saint-SacrementCentre de Recherche du CHU de QuébecQuebecCanada
  5. 5.Département d’Ophtalmologie, Faculté de MédecineUniversité LavalQuebecCanada
  6. 6.Centre Régional Léon Bérard de Lutte Contre le CancerLyonFrance
  7. 7.Centre de Recherche des CordeliersUniversité Pierre et Marie Curie – Paris 6ParisFrance
  8. 8.Université Paris DescartesParisFrance
  9. 9.INSERMParisFrance
  10. 10.Centre Oscart LambretLilleFrance
  11. 11.Service d’OphtalmologieCHU de CaenCaenFrance

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