Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074 (original) (raw)

Leukemia volume 18, pages 962–966 (2004)Cite this article

Abstract

The t(4;14)(p16.3;q32), associated with 10–20% of cases of multiple myeloma (MM), deregulates the expression of MMSET and FGFR3. To assess the potential of FGFR3 as a drug target, we evaluated the effects of selective inhibitors on MM and control cell lines. SU5402 and PD173074 specifically inhibited the growth of the two t(4;14)-positive MM lines, KMS-11 and OPM-2. Importantly, inhibition was still observed in the presence of IL-6, a growth factor known to play an important role in MM. Both compounds induced a dose-dependent reduction in cell viability and an increase in apoptosis, accompanied by a decrease in extracellular signal-related kinase phosphorylation. In contrast, no inhibition was seen with either compound against t(4;14)-negative cell lines or NCI-H929, a t(4;14)-positive, FGFR3-negative MM cell line. FGFR3 is thus a plausible candidate for targeted therapy in a subset of MM patients.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Chesi M, Nardin, E, Brents LA, Schrock E, Ried T, Kuehl WM et al. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 1997; 16: 260–264.
    Article CAS Google Scholar
  2. Giri D, Ropiquet F, Ittmann M . Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin Cancer Res 199; 5: 1063–1071.
    Google Scholar
  3. Onose H, Emoto N, Sugihara H, Shimizu K, Wakabayashi I . Overexpression of fibroblast growth factor receptor 3 in a human thyroid carcinoma cell line results in overgrowth of the confluent cultures. Eur J Endocrinol 1999; 140: 169–173.
    Article CAS Google Scholar
  4. Yoshimura N, Sano H, Hashiramoto A, Yamada R, Nakajima H, Kondo M et al. The expression and localization of fibroblast growth factor-1 (FGF-1) and FGF receptor-1 (FGFR1) in human breast cancer. Clin Immunol Immunopathol 1998; 89: 28–34.
    Article CAS Google Scholar
  5. Wagner M, Lopez ME, Cahn M, Korc M . Suppression of fibroblast growth factor receptor signalling inhibits pancreatic cancer growth in vitro and in vivo. Gastroenterology 1998; 114: 798–807.
    Article CAS Google Scholar
  6. Macdonald DHC, Reiter A, Cross NCP . The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1. Acta Haematol 2002; 107: 101–107.
    Article CAS Google Scholar
  7. Yagasaki F, Wakao D, Yokoyama Y, Uchida Y, Murohashi I, Kayano H et al. Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T-cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation. Cancer Res 2001; 61: 8371–8374.
    CAS PubMed Google Scholar
  8. Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet 1999; 23: 18–20.
    Article CAS Google Scholar
  9. Chesi M, Brents LA, Ely SA, Bais C, Robbiani DF, Mesri EA et al. Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. Blood 2001; 97: 729–736.
    Article CAS Google Scholar
  10. Soverini S, Terragna C, Testoni N, Ruggeri D, Tosi P, Zamagni E et al. Novel mutation and RNA splice variant of fibroblast growth factor receptor 3 in multiple myeloma patients at diagnosis. Haematologica 2002; 87: 1036–1040.
    CAS PubMed Google Scholar
  11. Sibley K, Fenton JA, Dring AM, Ashcroft AJ, Rawstron AC, Morgan GJ . A molecular study of the t(4;14) in multiple myeloma. Br J Haematol 2002; 118: 514–520.
    Article CAS Google Scholar
  12. Plowright EE, Li Z, Bergsagel PL, Chesi M, Barber DL, Branch DR et al. Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. Blood 2000; 95: 992–998.
    CAS Google Scholar
  13. Li Z, Zhu YX, Plowright EE, Bergsagel PL, Chesi M, Patterson B et al. The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells. Blood 2001; 97: 2413–2419.
    Article CAS Google Scholar
  14. Smedley D, Demiroglu A, Abdul-Rauf M, Heath C, Cooper C, Shipley J et al. ZNF198-FGFR1 transforms Ba/F3 cells to growth factor independence and results in high level tyrosine phosphorylation of STATS 1 and 5. Neoplasia 1999; 1: 349–355.
    Article CAS Google Scholar
  15. Laird AD, Vajkoczy P, Shawver LK, Thurnher A, Liang C, Mohammadi M et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 2000; 60: 4152–4160.
    CAS Google Scholar
  16. Mohammadi M, McMahon G, Sun L, Tang C, Hirth P, Yeh BK et al. Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science 1997; 276: 955–960.
    Article CAS Google Scholar
  17. Skaper SD, Kee WJ, Facci L, Macdonald G, Doherty P, Walsh FS . The FGFR1 inhibitor PD 173074 selectively and potently antagonizes FGF-2 neurotrophic and neurotropic effects. J Neurochem 2000; 75: 1520–1527.
    Article CAS Google Scholar
  18. Demiroglu A, Steer EJ, Heath C, Taylor K, Bentley M, Allen SL et al. The t(8;22) in chronic myeloid leukaemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins. Blood 2001; 98: 3778–3783.
    Article CAS Google Scholar
  19. Ronchetti D, Greco A, Compasso S, Colombo G, Dell’Era P, Otsuki T et al. Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations. Oncogene 2001; 20: 3553–3562.
    Article CAS Google Scholar
  20. Santra M, Zhan F, Tian E, Barlogie B, Shaughnessy Jr J . A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood 2003; 101: 2374–2376.
    Article CAS Google Scholar
  21. Keats JJ, Reiman T, Maxwell CA, Taylor BJ, Larratt LM, Mant MJ et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 2003; 101: 1520–1529.
    Article CAS Google Scholar

Download references

Acknowledgements

This work was supported by the British Society of Haematology Research Trust and the Leukaemia Research Fund.

Author information

Authors and Affiliations

  1. Wessex Regional Genetics Laboratory, Salisbury, UK
    E K Grand, A J Chase & N C P Cross
  2. Department of Haematology, Faculty of Medicine, Imperial College, London, UK
    E K Grand, C Heath & A Rahemtulla
  3. Human Genetics Division, University of Southampton School of Medicine, Southampton, UK
    A J Chase & N C P Cross

Authors

  1. E K Grand
    You can also search for this author inPubMed Google Scholar
  2. A J Chase
    You can also search for this author inPubMed Google Scholar
  3. C Heath
    You can also search for this author inPubMed Google Scholar
  4. A Rahemtulla
    You can also search for this author inPubMed Google Scholar
  5. N C P Cross
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toN C P Cross.

Rights and permissions

About this article

Cite this article

Grand, E., Chase, A., Heath, C. et al. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074.Leukemia 18, 962–966 (2004). https://doi.org/10.1038/sj.leu.2403347

Download citation

Keywords