Advertisement

Pathology & Oncology Research

, Volume 21, Issue 4, pp 957–968 | Cite as

Sensitivity of Melanoma Cells to EGFR and FGFR Activation but Not Inhibition is Influenced by Oncogenic BRAF and NRAS Mutations

  • Tamás Garay
  • Eszter Molnár
  • Éva Juhász
  • Viktória László
  • Tamás Barbai
  • Judit Dobos
  • Karin Schelch
  • Christine Pirker
  • Michael Grusch
  • Walter Berger
  • József Tímár
  • Balázs HegedűsEmail author
Research

Abstract

BRAF and NRAS are the two most frequent oncogenic driver mutations in melanoma and are pivotal components of both the EGF and FGF signaling network. Accordingly, we investigated the effect of BRAF and NRAS oncogenic mutation on the response to the stimulation and inhibition of epidermal and fibroblast growth factor receptors in melanoma cells. In the three BRAF mutant, two NRAS mutant and two double wild-type cell lines growth factor receptor expression had been verified by qRT-PCR. Cell proliferation and migration were determined by the analysis of 3-days-long time-lapse videomicroscopic recordings. Of note, a more profound response was found in motility as compared to proliferation and double wild-type cells displayed a higher sensitivity to EGF and FGF2 treatment when compared to mutant cells. Both baseline and induced activation of the growth factor signaling was assessed by immunoblot analysis of the phosphorylation of the downstream effectors Erk1/2. Low baseline and higher inducibility of the signaling pathway was characteristic in double wild-type cells. In contrast, oncogenic BRAF or NRAS mutation did not influence the response to EGF or FGF receptor inhibitors in vitro. Our findings demonstrate that the oncogenic mutations in melanoma have a profound impact on the motogenic effect of the activation of growth factor receptor signaling. Since emerging molecularly targeted therapies aim at the growth factor receptor signaling, the appropriate mutational analysis of individual melanoma cases is essential in both preclinical studies and in the clinical trials and practice.

Keywords

Melanoma BRAF NRAS Mutation EGF FGF2 EGFR inhibitor FGFR inhibitor 

Notes

Acknowledgments

This work was financially supported by TAMOP 4.2.1/B-09/1/MKR-2010-0001, OTKA CNK 77649 and MOB 80325 research grants as well as by the EGT/Norwegian Financial Mechanism HU0125. BH was a Magyary Zoltán postdoctoral fellow. GT acknowledges the Ernst Mach fellowship from the Österreichischer Austauschdienst.

Supplementary material

12253_2015_9916_MOESM1_ESM.doc (116 kb)
Supplementary Figure 1 (DOC 116 kb)
12253_2015_9916_MOESM2_ESM.doc (105 kb)
Supplementary Figure 2 (DOC 105 kb)

References

  1. 1.
    Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM (2006) Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 281(23):15694–15700. doi: 10.1074/jbc.M601252200 PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M (1996) Receptor specificity of the fibroblast growth factor family. J Biol Chem 271(25):15292–15297CrossRefPubMedGoogle Scholar
  3. 3.
    Heinzle C, Sutterluty H, Grusch M, Grasl-Kraupp B, Berger W, Marian B (2011) Targeting fibroblast-growth-factor-receptor-dependent signaling for cancer therapy. Expert Opin Ther Targets 15(7):829–846. doi: 10.1517/14728222.2011.566217 CrossRefPubMedGoogle Scholar
  4. 4.
    Harris RC, Chung E, Coffey RJ (2003) EGF receptor ligands. Exp Cell Res 284(1):2–13CrossRefPubMedGoogle Scholar
  5. 5.
    Dreux AC, Lamb DJ, Modjtahedi H, Ferns GA (2006) The epidermal growth factor receptors and their family of ligands: their putative role in atherogenesis. Atherosclerosis 186(1):38–53. doi: 10.1016/j.atherosclerosis.2005.06.038 CrossRefPubMedGoogle Scholar
  6. 6.
    Cotton LM, O’Bryan MK, Hinton BT (2008) Cellular signaling by fibroblast growth factors (FGFs) and their receptors (FGFRs) in male reproduction. Endocr Rev 29(2):193–216. doi: 10.1210/er.2007-0028 PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Maruta H, Burgess AW (1994) Regulation of the Ras signalling network. BioEssays: News Rev Mol Cell Dev Biol 16(7):489–496. doi: 10.1002/bies.950160708 CrossRefGoogle Scholar
  8. 8.
    Liang G, Liu Z, Wu J, Cai Y, Li X (2012) Anticancer molecules targeting fibroblast growth factor receptors. Trends Pharmacol Sci 33(10):531–541. doi: 10.1016/j.tips.2012.07.001 CrossRefPubMedGoogle Scholar
  9. 9.
    Ghosh P, Chin L (2009) Genetics and genomics of melanoma. Expert Rev Dermatol 4(2):131. doi: 10.1586/edm.09.2 PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Dutta PR, Maity A (2007) Cellular responses to EGFR inhibitors and their relevance to cancer therapy. Cancer Lett 254(2):165–177. doi: 10.1016/j.canlet.2007.02.006 PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, LeBoit PE, Pinkel D, Bastian BC (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353(20):2135–2147. doi: 10.1056/NEJMoa050092 CrossRefPubMedGoogle Scholar
  12. 12.
    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954. doi: 10.1038/nature00766 CrossRefPubMedGoogle Scholar
  13. 13.
    Demunter A, Stas M, Degreef H, De Wolf-Peeters C, van den Oord JJ (2001) Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma. J Invest Dermatol 117(6):1483–1489. doi: 10.1046/j.0022-202x.2001.01601.x CrossRefPubMedGoogle Scholar
  14. 14.
    Houben R, Becker JC, Kappel A, Terheyden P, Brocker EB, Goetz R, Rapp UR (2004) Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog 3(1):6. doi: 10.1186/1477-3163-3-6 PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Kumar R, Angelini S, Czene K, Sauroja I, Hahka-Kemppinen M, Pyrhonen S, Hemminki K (2003) BRAF mutations in metastatic melanoma: a possible association with clinical outcome. Clin Cancer Res 9(9):3362–3368PubMedGoogle Scholar
  16. 16.
    Maldonado JL, Fridlyand J, Patel H, Jain AN, Busam K, Kageshita T, Ono T, Albertson DG, Pinkel D, Bastian BC (2003) Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 95(24):1878–1890CrossRefPubMedGoogle Scholar
  17. 17.
    Tsao H, Goel V, Wu H, Yang G, Haluska FG (2004) Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol 122(2):337–341. doi: 10.1046/j.0022-202X.2004.22243.x PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Meier F, Schittek B, Busch S, Garbe C, Smalley K, Satyamoorthy K, Li G, Herlyn M (2005) The RAS/RAF/MEK/ERK and PI3K/AKT signaling pathways present molecular targets for the effective treatment of advanced melanoma. Front Biosci 10:2986–3001CrossRefPubMedGoogle Scholar
  19. 19.
    Sinnberg T, Lasithiotakis K, Niessner H, Schittek B, Flaherty KT, Kulms D, Maczey E, Campos M, Gogel J, Garbe C, Meier F (2009) Inhibition of PI3K-AKT-mTOR signaling sensitizes melanoma cells to cisplatin and temozolomide. J Invest Dermatol 129(6):1500–1515. doi: 10.1038/jid.2008.379 CrossRefPubMedGoogle Scholar
  20. 20.
    Collisson EA, De A, Suzuki H, Gambhir SS, Kolodney MS (2003) Treatment of metastatic melanoma with an orally available inhibitor of the Ras-Raf-MAPK cascade. Cancer Res 63(18):5669–5673PubMedGoogle Scholar
  21. 21.
    Carragher NO, Westhoff MA, Fincham VJ, Schaller MD, Frame MC (2003) A novel role for FAK as a protease-targeting adaptor protein: regulation by p42 ERK and Src. Curr Biol 13(16):1442–1450CrossRefPubMedGoogle Scholar
  22. 22.
    Lazar-Molnar E, Hegyesi H, Toth S, Falus A (2000) Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 12(6):547–554. doi: 10.1006/cyto.1999.0614 CrossRefPubMedGoogle Scholar
  23. 23.
    Feinmesser M, Veltman V, Morgenstern S, Tobar A, Gutman H, Kaganovsky E, Tzabari C, Sulkes J, Okon E (2010) Different patterns of expression of the erbB family of receptor tyrosine kinases in common nevi, dysplastic nevi, and primary malignant melanomas: an immunohistochemical study. Am J Dermatopathol 32(7):665–675. doi: 10.1097/DAD.0b013e3181d1e6f0 CrossRefPubMedGoogle Scholar
  24. 24.
    Boone B, Jacobs K, Ferdinande L, Taildeman J, Lambert J, Peeters M, Bracke M, Pauwels P, Brochez L (2011) EGFR in melanoma: clinical significance and potential therapeutic target. J Cutan Pathol 38(6):492–502. doi: 10.1111/j.1600-0560.2011.01673.x CrossRefPubMedGoogle Scholar
  25. 25.
    Rakosy Z, Vizkeleti L, Ecsedi S, Voko Z, Begany A, Barok M, Krekk Z, Gallai M, Szentirmay Z, Adany R, Balazs M (2007) EGFR gene copy number alterations in primary cutaneous malignant melanomas are associated with poor prognosis. Int J Cancer 121(8):1729–1737. doi: 10.1002/ijc.22928 CrossRefPubMedGoogle Scholar
  26. 26.
    Gordon-Thomson C, Mason RS, Moore GP (2001) Regulation of epidermal growth factor receptor expression in human melanocytes. Exp Dermatol 10(5):321–328CrossRefPubMedGoogle Scholar
  27. 27.
    Timar J, Gyorffy B, Raso E (2010) Gene signature of the metastatic potential of cutaneous melanoma: too much for too little? Clin Exp Metastasis 27(6):371–387. doi: 10.1007/s10585-010-9307-2 CrossRefPubMedGoogle Scholar
  28. 28.
    Bracher A, Cardona AS, Tauber S, Fink AM, Steiner A, Pehamberger H, Niederleithner H, Petzelbauer P, Groger M, Loewe R (2013) Epidermal growth factor facilitates melanoma lymph node metastasis by influencing tumor lymphangiogenesis. J Invest Dermatol 133(1):230–238. doi: 10.1038/jid.2012.272 CrossRefPubMedGoogle Scholar
  29. 29.
    Becker D, Lee PL, Rodeck U, Herlyn M (1992) Inhibition of the fibroblast growth factor receptor 1 (FGFR-1) gene in human melanocytes and malignant melanomas leads to inhibition of proliferation and signs indicative of differentiation. Oncogene 7(11):2303–2313PubMedGoogle Scholar
  30. 30.
    Easty DJ, Ganz SE, Farr CJ, Lai C, Herlyn M, Bennett DC (1993) Novel and known protein tyrosine kinases and their abnormal expression in human melanoma. J Invest Dermatol 101(5):679–684CrossRefPubMedGoogle Scholar
  31. 31.
    Yayon A, Ma YS, Safran M, Klagsbrun M, Halaban R (1997) Suppression of autocrine cell proliferation and tumorigenesis of human melanoma cells and fibroblast growth factor transformed fibroblasts by a kinase-deficient FGF receptor 1: evidence for the involvement of Src-family kinases. Oncogene 14(25):2999–3009. doi: 10.1038/sj.onc.1201159 CrossRefPubMedGoogle Scholar
  32. 32.
    Streit S, Mestel DS, Schmidt M, Ullrich A, Berking C (2006) FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients. Br J Cancer 94(12):1879–1886. doi: 10.1038/sj.bjc.6603181 PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Gartside MG, Chen H, Ibrahimi OA, Byron SA, Curtis AV, Wellens CL, Bengston A, Yudt LM, Eliseenkova AV, Ma J, Curtin JA, Hyder P, Harper UL, Riedesel E, Mann GJ, Trent JM, Bastian BC, Meltzer PS, Mohammadi M, Pollock PM (2009) Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma. Mol Cancer Res 7(1):41–54. doi: 10.1158/1541-7786.mcr-08-0021 PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Halaban R, Langdon R, Birchall N, Cuono C, Baird A, Scott G, Moellmann G, McGuire J (1988) Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes. J Cell Biol 107(4):1611–1619CrossRefPubMedGoogle Scholar
  35. 35.
    Dotto GP, Moellmann G, Ghosh S, Edwards M, Halaban R (1989) Transformation of murine melanocytes by basic fibroblast growth factor cDNA and oncogenes and selective suppression of the transformed phenotype in a reconstituted cutaneous environment. J Cell Biol 109(6 Pt 1):3115–3128CrossRefPubMedGoogle Scholar
  36. 36.
    Nesbit M, Nesbit HK, Bennett J, Andl T, Hsu MY, Dejesus E, McBrian M, Gupta AR, Eck SL, Herlyn M (1999) Basic fibroblast growth factor induces a transformed phenotype in normal human melanocytes. Oncogene 18(47):6469–6476. doi: 10.1038/sj.onc.1203066 CrossRefPubMedGoogle Scholar
  37. 37.
    Wang Y, Becker D (1997) Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nat Med 3(8):887–893CrossRefPubMedGoogle Scholar
  38. 38.
    Chalkiadaki G, Nikitovic D, Berdiaki A, Sifaki M, Krasagakis K, Katonis P, Karamanos NK, Tzanakakis GN (2009) Fibroblast growth factor-2 modulates melanoma adhesion and migration through a syndecan-4-dependent mechanism. Int J Biochem Cell Biol 41(6):1323–1331. doi: 10.1016/j.biocel.2008.11.008 CrossRefPubMedGoogle Scholar
  39. 39.
    Becker D, Meier CB, Herlyn M (1989) Proliferation of human malignant melanomas is inhibited by antisense oligodeoxynucleotides targeted against basic fibroblast growth factor. EMBO J 8(12):3685–3691PubMedCentralPubMedGoogle Scholar
  40. 40.
    Ozen M, Medrano EE, Ittmann M (2004) Inhibition of proliferation and survival of melanoma cells by adenoviral-mediated expression of dominant negative fibroblast growth factor receptor. Melanoma Res 14(1):13–21CrossRefPubMedGoogle Scholar
  41. 41.
    Li D, Wang H, Xiang JJ, Deng N, Wang PP, Kang YL, Tao J, Xu M (2010) Monoclonal antibodies targeting basic fibroblast growth factor inhibit the growth of B16 melanoma in vivo and in vitro. Oncol Rep 24(2):457–463PubMedGoogle Scholar
  42. 42.
    Blanco Codesido M, Tesainer Brunetto A, Frentzas S, Moreno Garcia V, Papadatos-Pastos D, Pedersen JV, Trani L, Puglisi M, Molife LR, Banerji U (2011) Outcomes of patients with metastatic melanoma treated with molecularly targeted agents in phase I clinical trials. Oncology 81(2):135–140. doi: 10.1159/000330206 CrossRefPubMedGoogle Scholar
  43. 43.
    Ji Z, Flaherty KT, Tsao H (2012) Targeting the RAS pathway in melanoma. Trends Mol Med 18(1):27–35. doi: 10.1016/j.molmed.2011.08.001 PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Djerf EA, Trinks C, Abdiu A, Thunell LK, Hallbeck AL, Walz TM (2009) ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839). Melanoma Res 19(3):156–166. doi: 10.1097/CMR.0b013e32832c6339 CrossRefPubMedGoogle Scholar
  45. 45.
    Patel SP, Kim KB, Papadopoulos NE, Hwu WJ, Hwu P, Prieto VG, Bar-Eli M, Zigler M, Dobroff A, Bronstein Y, Bassett RL, Vardeleon AG, Bedikian AY (2011) A phase II study of gefitinib in patients with metastatic melanoma. Melanoma Res 21(4):357–363. doi: 10.1097/CMR.0b013e3283471073 PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Schicher N, Paulitschke V, Swoboda A, Kunstfeld R, Loewe R, Pilarski P, Pehamberger H, Hoeller C (2009) Erlotinib and bevacizumab have synergistic activity against melanoma. Clin Cancer Res 15(10):3495–3502. doi: 10.1158/1078-0432.ccr-08-2407 CrossRefPubMedGoogle Scholar
  47. 47.
    Djerf Severinsson EA, Trinks C, Green H, Abdiu A, Hallbeck AL, Stal O, Walz TM (2011) The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo. Biochem Biophys Res Commun 414(3):563–568. doi: 10.1016/j.bbrc.2011.09.118 CrossRefPubMedGoogle Scholar
  48. 48.
    Kim H, Lim HY (2011) Novel EGFR-TK inhibitor EKB-569 inhibits hepatocellular carcinoma cell proliferation by AKT and MAPK pathways. J Korean Med Sci 26(12):1563–1568. doi: 10.3346/jkms.2011.26.12.1563 PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher KJ, Settleman J, Haber DA (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 102(21):7665–7670. doi: 10.1073/pnas.0502860102 PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Bryce AH, Rao R, Sarkaria J, Reid JM, Qi Y, Qin R, James CD, Jenkins RB, Boni J, Erlichman C, Haluska P (2012) Phase I study of temsirolimus in combination with EKB-569 in patients with advanced solid tumors. Investig New Drugs 30(5):1934–1941. doi: 10.1007/s10637-011-9742-1 CrossRefGoogle Scholar
  51. 51.
    Metzner T, Bedeir A, Held G, Peter-Vorosmarty B, Ghassemi S, Heinzle C, Spiegl-Kreinecker S, Marian B, Holzmann K, Grasl-Kraupp B, Pirker C, Micksche M, Berger W, Heffeter P, Grusch M (2011) Fibroblast growth factor receptors as therapeutic targets in human melanoma: synergism with BRAF inhibition. J Invest Dermatol 131(10):2087–2095. doi: 10.1038/jid.2011.177 PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Torok S, Cserepes TM, Renyi-Vamos F, Dome B (2012) Nintedanib (BIBF 1120) in the treatment of solid cancers: an overview of biological and clinical aspects. Magy Onkol 56(3):199–208, doi:MagyOnkol.2012.56.3.199PubMedGoogle Scholar
  53. 53.
    Katoh M, Nakagama H (2013) FGF receptors: cancer biology and therapeutics. Med Res Rev. doi: 10.1002/med.21288 PubMedGoogle Scholar
  54. 54.
    Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68(12):4774–4782. doi: 10.1158/0008-5472.can-07-6307 CrossRefPubMedGoogle Scholar
  55. 55.
    O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16(5):401–412. doi: 10.1016/j.ccr.2009.09.028 PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Gozgit JM, Wong MJ, Moran L, Wardwell S, Mohemmad QK, Narasimhan NI, Shakespeare WC, Wang F, Clackson T, Rivera VM (2012) Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol Cancer Ther 11(3):690–699. doi: 10.1158/1535-7163.mct-11-0450 CrossRefPubMedGoogle Scholar
  57. 57.
    Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, Brueggen J, Jensen MR, Schnell C, Schmid H, Wartmann M, Berghausen J, Drueckes P, Zimmerlin A, Bussiere D, Murray J, Graus Porta D (2011) Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamin o]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem 54(20):7066–7083. doi: 10.1021/jm2006222 CrossRefPubMedGoogle Scholar
  58. 58.
    Cheng T, Roth B, Choi W, Black PC, Dinney C, McConkey DJ (2013) Fibroblast growth factor receptors-1 and -3 play distinct roles in the regulation of bladder cancer growth and metastasis: implications for therapeutic targeting. PLoS One 8(2):e57284. doi: 10.1371/journal.pone.0057284 PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, Rooney C, Coleman T, Baker D, Mellor MJ, Brooks AN, Klinowska T (2012) AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res 72(8):2045–2056. doi: 10.1158/0008-5472.can-11-3034 CrossRefPubMedGoogle Scholar
  60. 60.
    Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong XQ, Buchanan S, Henry JR, Starling JJ, Peng SB (2012) Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem 287(33):28087–28098. doi: 10.1074/jbc.M112.377218 PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, Zambon A, Sinclair J, Hayes A, Gore M, Lorigan P, Springer C, Larkin J, Jorgensen C, Marais R (2013) Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer discovery 3(2):158–167. doi: 10.1158/2159-8290.cd-12-0386 CrossRefPubMedGoogle Scholar
  62. 62.
    Mueller BM, Romerdahl CA, Trent JM, Reisfeld RA (1991) Suppression of spontaneous melanoma metastasis in scid mice with an antibody to the epidermal growth factor receptor. Cancer Res 51(8):2193–2198PubMedGoogle Scholar
  63. 63.
    Ladanyi A, Gallai M, Paku S, Nagy JO, Dudas J, Timar J, Kovalszky I (2001) Expression of a decorin-like moleculein human melanoma. Pathol Oncol Res 7(4):260–266CrossRefPubMedGoogle Scholar
  64. 64.
    Berger W, Elbling L, Minai-Pour M, Vetterlein M, Pirker R, Kokoschka EM, Micksche M (1994) Intrinsic MDR-1 gene and P-glycoprotein expression in human melanoma cell lines. Int J Cancer 59(5):717–723CrossRefPubMedGoogle Scholar
  65. 65.
    Garay T, Juhasz E, Molnar E, Eisenbauer M, Czirok A, Dekan B, Laszlo V, Hoda MA, Dome B, Timar J, Klepetko W, Berger W, Hegedus B (2013) Cell migration or cytokinesis and proliferation? - revisiting the “go or grow” hypothesis in cancer cells in vitro. Exp Cell Res. doi: 10.1016/j.yexcr.2013.08.018 Google Scholar
  66. 66.
    Hegedus B, Zach J, Czirok A, Lovey J, Vicsek T (2004) Irradiation and Taxol treatment result in non-monotonous, dose-dependent changes in the motility of glioblastoma cells. J Neuro-Oncol 67(1–2):147–157CrossRefGoogle Scholar
  67. 67.
    Easty DJ, Gray SG, O’Byrne KJ, O’Donnell D, Bennett DC (2011) Receptor tyrosine kinases and their activation in melanoma. Pigment Cell Melanoma Res 24(3):446–461. doi: 10.1111/j.1755-148X.2011.00836.x CrossRefPubMedGoogle Scholar
  68. 68.
    Jakob JA, Bassett RL Jr, Ng CS, Curry JL, Joseph RW, Alvarado GC, Rohlfs ML, Richard J, Gershenwald JE, Kim KB, Lazar AJ, Hwu P, Davies MA (2012) NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 118(16):4014–4023. doi: 10.1002/cncr.26724 PubMedCentralCrossRefPubMedGoogle Scholar
  69. 69.
    Safaee Ardekani G, Jafarnejad SM, Tan L, Saeedi A, Li G (2012) The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One 7(10):e47054. doi: 10.1371/journal.pone.0047054 PubMedCentralCrossRefPubMedGoogle Scholar
  70. 70.
    Houben R, Vetter-Kauczok CS, Ortmann S, Rapp UR, Broecker EB, Becker JC (2008) Phospho-ERK staining is a poor indicator of the mutational status of BRAF and NRAS in human melanoma. J Invest Dermatol 128(8):2003–2012. doi: 10.1038/jid.2008.30 CrossRefPubMedGoogle Scholar
  71. 71.
    Yazdi AS, Ghoreschi K, Sander CA, Rocken M (2010) Activation of the mitogen-activated protein kinase pathway in malignant melanoma can occur independently of the BRAF T1799A mutation. Eur J Dermatol EJD 20(5):575–579. doi: 10.1684/ejd.2010.1011 PubMedGoogle Scholar
  72. 72.
    Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehar J, Kryukov GV, Sonkin D, Reddy A, Liu M, Murray L, Berger MF, Monahan JE, Morais P, Meltzer J, Korejwa A, Jane-Valbuena J, Mapa FA, Thibault J, Bric-Furlong E, Raman P, Shipway A, Engels IH, Cheng J, Yu GK, Yu J, Aspesi P Jr, de Silva M, Jagtap K, Jones MD, Wang L, Hatton C, Palescandolo E, Gupta S, Mahan S, Sougnez C, Onofrio RC, Liefeld T, MacConaill L, Winckler W, Reich M, Li N, Mesirov JP, Gabriel SB, Getz G, Ardlie K, Chan V, Myer VE, Weber BL, Porter J, Warmuth M, Finan P, Harris JL, Meyerson M, Golub TR, Morrissey MP, Sellers WR, Schlegel R, Garraway LA (2012) The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483(7391):603–607. doi: 10.1038/nature11003 PubMedCentralCrossRefPubMedGoogle Scholar
  73. 73.
    Kim KB, Chesney J, Robinson D, Gardner H, Shi MM, Kirkwood JM (2011) Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma. Clin Cancer Res 17(23):7451–7461. doi: 10.1158/1078-0432.ccr-11-1747 CrossRefPubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2015

Authors and Affiliations

  • Tamás Garay
    • 1
  • Eszter Molnár
    • 1
  • Éva Juhász
    • 1
  • Viktória László
    • 2
  • Tamás Barbai
    • 1
  • Judit Dobos
    • 3
    • 4
  • Karin Schelch
    • 5
  • Christine Pirker
    • 5
  • Michael Grusch
    • 5
  • Walter Berger
    • 5
  • József Tímár
    • 1
    • 6
  • Balázs Hegedűs
    • 1
    • 2
    • 6
    Email author
  1. 1.2nd Department of PathologySemmelweis UniversityBudapestHungary
  2. 2.Department of Thoracic SurgeryMedical University of ViennaViennaAustria
  3. 3.Department of Experimental PharmacologyNational Institute of OncologyBudapestHungary
  4. 4.Vichem Chemie Research LtdBudapestHungary
  5. 5.Institute of Cancer Research and Comprehensive Cancer CenterMedical University of ViennaViennaAustria
  6. 6.MTA-SE Tumor Progression Research GroupBudapestHungary

Personalised recommendations