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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 Mouriaux
Research Paper

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.

Keywords

Uveal melanoma Imatinib mesylate Metastasis KIT Stem cell factor Targeted therapy 

Notes

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.

References

  1. 1.
    Singh AD, Turell ME, Topham AK (2011) Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology 118:1881–1885PubMedCrossRefGoogle Scholar
  2. 2.
    Hawkins BS (2011) Collaborative ocular melanoma study randomized trial of I-125 brachytherapy. Clin Trials 8:661–673PubMedCrossRefGoogle Scholar
  3. 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 330:1410–1413PubMedCentralPubMedCrossRefGoogle Scholar
  4. 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 61:3439–3442PubMedGoogle Scholar
  5. 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 12:461–468PubMedCentralPubMedCrossRefGoogle Scholar
  6. 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 119:670–676CrossRefGoogle Scholar
  7. 7.
    Augsburger JJ, Correa ZM, Shaikh AH (2009) Effectiveness of treatments for metastatic uveal melanoma. Am J Ophthalmol 148:119–127PubMedCrossRefGoogle Scholar
  8. 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 83:1771–1776PubMedCrossRefGoogle Scholar
  9. 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 92:2032–2038PubMedCentralPubMedCrossRefGoogle Scholar
  10. 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 49:5230–5234PubMedCentralPubMedCrossRefGoogle Scholar
  11. 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 457:599–602PubMedCentralPubMedCrossRefGoogle Scholar
  12. 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 363:2191–2199PubMedCentralPubMedCrossRefGoogle Scholar
  13. 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 4:19PubMedCentralPubMedCrossRefGoogle Scholar
  14. 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 279:31769–31779PubMedCrossRefGoogle Scholar
  15. 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 13:161–166PubMedCrossRefGoogle Scholar
  16. 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 73:151–157PubMedCrossRefGoogle Scholar
  17. 17.
    Capdeville R, Buchdunger E, Zimmermann J, Matter A (2002) Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 1:493–502PubMedCrossRefGoogle Scholar
  18. 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 295:139–145PubMedGoogle Scholar
  19. 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 96:925–932PubMedGoogle Scholar
  20. 20.
    Deininger M, Buchdunger E, Druker BJ (2005) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105:2640–2653PubMedCrossRefGoogle Scholar
  21. 21.
    Mauro MJ, O’Dwyer M, Heinrich MC, Druker BJ (2002) STI571: a paradigm of new agents for cancer therapeutics. J Clin Oncol 20:325–334PubMedCrossRefGoogle Scholar
  22. 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 10:681–690PubMedCrossRefGoogle Scholar
  23. 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 14:805PubMedCrossRefGoogle Scholar
  24. 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 26:561–565PubMedCrossRefGoogle Scholar
  25. 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 15:324–329PubMedCrossRefGoogle Scholar
  26. 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 443:741–744PubMedCrossRefGoogle Scholar
  27. 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 96:502–509PubMedGoogle Scholar
  28. 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 39:876–884PubMedGoogle Scholar
  29. 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 30:829–834PubMedGoogle Scholar
  30. 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 62:155–161PubMedCrossRefGoogle Scholar
  31. 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 15:509–518PubMedCrossRefGoogle Scholar
  32. 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 15:257–266PubMedCrossRefGoogle Scholar
  33. 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 49:4697–4701PubMedCentralPubMedCrossRefGoogle Scholar
  34. 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 19:233–246PubMedCrossRefGoogle Scholar
  35. 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 281:9238–9250PubMedCrossRefGoogle Scholar
  36. 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 64:1025–1035PubMedCrossRefGoogle Scholar
  37. 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 52:197–201PubMedCrossRefGoogle Scholar
  38. 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 106:2005–2011PubMedCrossRefGoogle Scholar
  39. 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 22:935–942PubMedCrossRefGoogle Scholar
  40. 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 7:1121–1129PubMedCentralPubMedCrossRefGoogle Scholar
  41. 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 80:1750–1757PubMedGoogle Scholar
  42. 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 279:31655–31663PubMedCrossRefGoogle Scholar
  43. 43.
    Lennartsson J, Ronnstrand L (2012) Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev 92:1619–1649PubMedCrossRefGoogle Scholar
  44. 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 86:440–447PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Lee JT, Herlyn M (2007) Microenvironmental influences in melanoma progression. J Cell Biochem 101:862–872PubMedCrossRefGoogle Scholar

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
  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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