Skip to main content

Advertisement

SpringerLink
Log in

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

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Singh AD, Turell ME, Topham AK (2011) Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology 118:1881–1885

    Article  PubMed  Google Scholar 

  2. Hawkins BS (2011) Collaborative ocular melanoma study randomized trial of I-125 brachytherapy. Clin Trials 8:661–673

    Article  PubMed  Google Scholar 

  3. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM (2010) Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330:1410–1413

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Tschentscher F, Prescher G, Horsman DE, White VA, Rieder H, Anastassiou G, Schilling H, Bornfeld N, Bartz-Schmidt KU, Horsthemke B, Lohmann DR, Zeschnigk M (2001) Partial deletions of the long and short arm of chromosome 3 point to two tumor suppressor genes in uveal melanoma. Cancer Res 61:3439–3442

    CAS  PubMed  Google Scholar 

  5. Onken MD, Worley LA, Tuscan MD, Harbour JW (2010) An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn 12:461–468

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Collaborative Ocular Melanoma Study Group (2001) Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the collaborative ocular melanoma study (COMS): COMS report no. 15. Arch Ophthalmol 119:670–676

    Article  Google Scholar 

  7. Augsburger JJ, Correa ZM, Shaikh AH (2009) Effectiveness of treatments for metastatic uveal melanoma. Am J Ophthalmol 148:119–127

    Article  PubMed  Google Scholar 

  8. Weber A, Hengge UR, Urbanik D, Markwart A, Mirmohammadsaegh A, Reichel MB, Wittekind C, Wiedemann P, Tannapfel A (2003) Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. Lab Invest 83:1771–1776

    Article  CAS  PubMed  Google Scholar 

  9. Zuidervaart W, van Nieuwpoort F, Stark M, Dijkman R, Packer L, Borgstein AM, Pavey S, van der Velden P, Out C, Jager MJ, Hayward NK, Gruis NA (2005) Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS. Br J Cancer 92:2032–2038

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM, Harbour JW (2008) Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci 49:5230–5234

    Article  PubMed Central  PubMed  Google Scholar 

  11. Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O’Brien JM, Simpson EM, Barsh GS, Bastian BC (2009) Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457:599–602

    Article  PubMed Central  PubMed  Google Scholar 

  12. Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, Obenauf AC, Wackernagel W, Green G, Bouvier N, Sozen MM, Baimukanova G, Roy R, Heguy A, Dolgalev I, Khanin R, Busam K, Speicher MR, O’Brien J, Bastian BC (2010) Mutations in GNA11 in uveal melanoma. N Engl J Med 363:2191–2199

    Article  PubMed Central  PubMed  Google Scholar 

  13. Pereira PR, Odashiro AN, Marshall JC, Correa ZM, Belfort R Jr, Burnier MN Jr (2005) The role of c-kit and imatinib mesylate in uveal melanoma. J Carcinog 4:19

    Article  PubMed Central  PubMed  Google Scholar 

  14. Lefevre G, Glotin AL, Calipel A, Mouriaux F, Tran T, Kherrouche Z, Maurage CA, Auclair C, Mascarelli F (2004) Roles of stem cell factor/c-Kit and effects of Glivec/STI571 in human uveal melanoma cell tumorigenesis. J Biol Chem 279:31769–31779

    Article  CAS  PubMed  Google Scholar 

  15. Mouriaux F, Kherrouche Z, Maurage CA, Demailly FX, Labalette P, Saule S (2003) Expression of the c-kit receptor in choroidal melanomas. Melanoma Res 13:161–166

    Article  CAS  PubMed  Google Scholar 

  16. Mouriaux F, Chahud F, Maurage CA, Malecaze F, Labalette P (2001) Implication of stem cell factor in the proliferation of choroidal melanocytes. Exp Eye Res 73:151–157

    Article  CAS  PubMed  Google Scholar 

  17. Capdeville R, Buchdunger E, Zimmermann J, Matter A (2002) Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 1:493–502

    Article  CAS  PubMed  Google Scholar 

  18. Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295:139–145

    CAS  PubMed  Google Scholar 

  19. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ (2000) Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96:925–932

    CAS  PubMed  Google Scholar 

  20. Deininger M, Buchdunger E, Druker BJ (2005) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105:2640–2653

    Article  CAS  PubMed  Google Scholar 

  21. Mauro MJ, O’Dwyer M, Heinrich MC, Druker BJ (2002) STI571: a paradigm of new agents for cancer therapeutics. J Clin Oncol 20:325–334

    Article  CAS  PubMed  Google Scholar 

  22. Matei D, Chang DD, Jeng MH (2004) Imatinib mesylate (Gleevec) inhibits ovarian cancer cell growth through a mechanism dependent on platelet-derived growth factor receptor alpha and Akt inactivation. Clin Cancer Res 10:681–690

    Article  CAS  PubMed  Google Scholar 

  23. Fiorentini G, Rossi S, Lanzanova G, Bernardeschi P, Dentico P, De Giorgi U (2003) Potential use of imatinib mesylate in ocular melanoma and liposarcoma expressing immunohistochemical c-KIT (CD117). Ann Oncol 14:805

    Article  CAS  PubMed  Google Scholar 

  24. Penel N, Delcambre C, Durando X, Clisant S, Hebbar M, Negrier S, Fournier C, Isambert N, Mascarelli F, Mouriaux F (2008) O-Mel-Inib: a Cancero-pole Nord-Ouest multicenter phase II trial of high-dose imatinib mesylate in metastatic uveal melanoma. Invest New Drugs 26:561–565

    Article  CAS  PubMed  Google Scholar 

  25. Hofmann UB, Kauczok-Vetter CS, Houben R, Becker JC (2009) Overexpression of the KIT/SCF in uveal melanoma does not translate into clinical efficacy of imatinib mesylate. Clin Cancer Res 15:324–329

    Article  CAS  PubMed  Google Scholar 

  26. Pache M, Glatz K, Bosch D, Dirnhofer S, Mirlacher M, Simon R, Schraml P, Rufle A, Flammer J, Sauter G, Meyer P (2003) Sequence analysis and high-throughput immunohistochemical profiling of KIT (CD 117) expression in uveal melanoma using tissue microarrays. Virchows Arch 443:741–744

    Article  CAS  PubMed  Google Scholar 

  27. McLean IW, Foster WD, Zimmerman LE, Gamel JW (1983) Modifications of Callender’s classification of uveal melanoma at the armed forces institute of pathology. Am J Ophthalmol 96:502–509

    CAS  PubMed  Google Scholar 

  28. Mouriaux F, Casagrande F, Pillaire MJ, Manenti S, Malecaze F, Darbon JM (1998) Differential expression of G1 cyclins and cyclin-dependent kinase inhibitors in normal and transformed melanocytes. Invest Ophthalmol Vis Sci 39:876–884

    CAS  PubMed  Google Scholar 

  29. Kan-Mitchell J, Mitchell MS, Rao N, Liggett PE (1989) Characterization of uveal melanoma cell lines that grow as xenografts in rabbit eyes. Invest Ophthalmol Vis Sci 30:829–834

    CAS  PubMed  Google Scholar 

  30. De Waard-Siebinga I, Blom DJ, Griffioen M, Schrier PI, Hoogendoorn E, Beverstock G, Danen EH, Jager MJ (1995) Establishment and characterization of an uveal-melanoma cell line. Int J Cancer 62:155–161

    Article  PubMed  Google Scholar 

  31. Chen PW, Murray TG, Uno T, Salgaller ML, Reddy R, Ksander BR (1997) Expression of MAGE genes in ocular melanoma during progression from primary to metastatic disease. Clin Exp Metastasis 15:509–518

    Article  CAS  PubMed  Google Scholar 

  32. Labialle S, Dayan G, Gambrelle J, Gayet L, Barakat S, Devouassoux-Shisheboran M, Bernaud J, Rigal D, Grange JD, Baggetto LG (2005) Characterization of the typical multidrug resistance profile in human uveal melanoma cell lines and in mouse liver metastasis derivatives. Melanoma Res 15:257–266

    Article  CAS  PubMed  Google Scholar 

  33. Folberg R, Kadkol SS, Frenkel S, Valyi-Nagy K, Jager MJ, Pe’er J, Maniotis AJ (2008) Authenticating cell lines in ophthalmic research laboratories. Invest Ophthalmol Vis Sci 49:4697–4701

    Article  PubMed Central  PubMed  Google Scholar 

  34. Seftor EA, Meltzer PS, Kirschmann DA, Pe’er J, Maniotis AJ, Trent JM, Folberg R, Hendrix MJ (2002) Molecular determinants of human uveal melanoma invasion and metastasis. Clin Exp Metastasis 19:233–246

    Article  CAS  PubMed  Google Scholar 

  35. Calipel A, Mouriaux F, Glotin AL, Malecaze F, Faussat AM, Mascarelli F (2006) Extracellular signal-regulated kinase-dependent proliferation is mediated through the protein kinase A/B-Raf pathway in human uveal melanoma cells. J Biol Chem 281:9238–9250

    Article  CAS  PubMed  Google Scholar 

  36. Flanagan JG, Chan DC, Leder P (1991) Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant. Cell 64:1025–1035

    Article  CAS  PubMed  Google Scholar 

  37. Natali PG, Nicotra MR, Winkler AB, Cavaliere R, Bigotti A, Ullrich A (1992) Progression of human cutaneous melanoma is associated with loss of expression of c-kit proto-oncogene receptor. Int J Cancer 52:197–201

    Article  CAS  PubMed  Google Scholar 

  38. Wyman K, Atkins MB, Prieto V, Eton O, McDermott DF, Hubbard F, Byrnes C, Sanders K, Sosman JA (2006) Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 106:2005–2011

    Article  CAS  PubMed  Google Scholar 

  39. Peng B, Hayes M, Resta D, Racine-Poon A, Druker BJ, Talpaz M, Sawyers CL, Rosamilia M, Ford J, Lloyd P, Capdeville R (2004) Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 22:935–942

    Article  CAS  PubMed  Google Scholar 

  40. Weisberg E, Wright RD, McMillin DW, Mitsiades C, Ray A, Barrett R, Adamia S, Stone R, Galinsky I, Kung AL, Griffin JD (2008) Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia cells. Mol Cancer Ther 7:1121–1129

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Lotem J, Sachs L (1992) Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells. Blood 80:1750–1757

    CAS  PubMed  Google Scholar 

  42. Mol CD, Dougan DR, Schneider TR, Skene RJ, Kraus ML, Scheibe DN, Snell GP, Zou H, Sang BC, Wilson KP (2004) Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem 279:31655–31663

    Article  CAS  PubMed  Google Scholar 

  43. Lennartsson J, Ronnstrand L (2012) Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev 92:1619–1649

    Article  CAS  PubMed  Google Scholar 

  44. Boyd SR, Tan DS, de Souza L, Neale MH, Myatt NE, Alexander RA, Robb M, Hungerford JL, Cree IA (2002) Uveal melanomas express vascular endothelial growth factor and basic fibroblast growth factor and support endothelial cell growth. Br J Ophthalmol 86:440–447

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Lee JT, Herlyn M (2007) Microenvironmental influences in melanoma progression. J Cell Biochem 101:862–872

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. CNRS, UMR 6301 ISTCT, CERVOxy. GIP CYCERON, 14074, Caen, France

    Armelle Calipel & Frédéric Mouriaux

  2. CEA, DSV/I2BM, UMR 6301 ISTCT, 14074, Caen, France

    Armelle Calipel & Frédéric Mouriaux

  3. Université de Caen Basse-Normandie, UMR 6301 ISTCT, 14074, Caen, France

    Armelle Calipel & Frédéric Mouriaux

  4. Centre universitaire d’ophtalmologie-Recherche, Hôpital du Saint-Sacrement, Centre de Recherche du CHU de Québec, Quebec, QC, Canada

    Solange Landreville & Frédéric Mouriaux

  5. Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Quebec, QC, Canada

    Solange Landreville & Frédéric Mouriaux

  6. Centre Régional Léon Bérard de Lutte Contre le Cancer, 69373, Lyon, France

    Arnaud De La Fouchardière & Michel Rivoire

  7. Centre de Recherche des Cordeliers, Université Pierre et Marie Curie – Paris 6, UMR S 872, 75006, Paris, France

    Frédéric Mascarelli

  8. Université Paris Descartes, UMR S 872, 75006, Paris, France

    Frédéric Mascarelli

  9. INSERM, U872, 75006, Paris, France

    Frédéric Mascarelli

  10. Centre Oscart Lambret, 3, Rue F Combemale, 59020, Lille, France

    Nicolas Penel

  11. Service d’Ophtalmologie, CHU de Caen, 14000, Caen, France

    Frédéric Mouriaux

Authors
  1. Armelle Calipel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Solange Landreville
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arnaud De La Fouchardière
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frédéric Mascarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michel Rivoire
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nicolas Penel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Frédéric Mouriaux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frédéric Mouriaux.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Calipel, A., Landreville, S., De La Fouchardière, A. et al. Mechanisms of resistance to imatinib mesylate in KIT-positive metastatic uveal melanoma. Clin Exp Metastasis 31, 553–564 (2014). https://doi.org/10.1007/s10585-014-9649-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-014-9649-2

Keywords

Search

Navigation