title: Mechanisms of resistance to imatinib mesylate in KIT-positive metastatic uveal melanoma.
abstract: 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.
authors.affiliation: CNRS, UMR 6301 ISTCT, CERVOxy. GIP CYCERON, 14074, Caen, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Calipel
authors.forename: Solange
authors.initials: S
authors.lastname: Landreville
authors.forename: Arnaud
authors.initials: A
authors.lastname: De La Fouchardière
authors.forename: Frédéric
authors.initials: F
authors.lastname: Mascarelli
authors.forename: Michel
authors.initials: M
authors.lastname: Rivoire
authors.forename: Nicolas
authors.initials: N
authors.lastname: Penel
authors.forename: Frédéric
authors.initials: F
authors.lastname: Mouriaux
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D000068877:Imatinib Mesylate; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D019089:Stem Cell Factor / Q000235:genetics; D016896:Treatment Outcome; D014604:Uveal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D000098943:Uveal Melanoma
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor