Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies

Abstract

Reccurent chromosomal translocation t(4;14) (p16.3;q32.3) occurs in patients with multiple myeloma (MM) and is associated with ectopic overexpression of fibroblast growth factor receptor 3 (FGFR3) that sometimes may contain the activation mutations such as K650E thanatophoric dysplasia type II (TDII). Although there have been significant advances in therapy for MM including the use of proteasome inhibitors, t(4;14) MM has a particularly poor prognosis and most patients still die from complications related to their disease or therapy. One potential therapeutic strategy is to inhibit FGFR3 in those myeloma patients that overexpress the receptor tyrosine kinase due to chromosomal translocation. Here we evaluated PKC412, a small molecule tyrosine kinase inhibitor, for treatment of FGFR3-induced hematopoietic malignancies. PKC412 inhibited kinase activation and proliferation of hematopoietic Ba/F3 cells transformed by FGFR3 TDII or a TEL-FGFR3 fusion. Similar results were obtained in PKC412 inhibition of several different t(4;14)-positive human MM cell lines. Furthermore, treatment with PKC412 resulted in a statistically significant prolongation of survival in murine bone marrow transplant models of FGFR3 TDII-induced pre-B cell lymphoma, or a peripheral T-cell lymphoma associated TEL-FGFR3 fusion-induced myeloproliferative disease. These data indicate that PKC412 may be a useful molecularly targeted therapy for MM associated with overexpression of FGFR3, and perhaps other diseases associated with dysregulation of FGFR3 or related mutants.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Andrejauskas-Buchdunger E and Regenass U . (1992). Cancer Res., 52, 5353–5358.

  • Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, Chase A, Chessells JM, Colombat M, Dearden CE, Dimitrijevic S, Mahon FX, Marin D, Nikolova Z, Olavarria E, Silberman S, Schultheis B, Cross NC and Goldman JM . (2002). N. Engl. J. Med., 347, 481–487.

  • Bastuji-Garin S, Ochonisky S, Bouche P, Gherardi RK, Duguet C, Djerradine Z, Poli F and Revuz J . (2002). J. Invest. Dermatol., 119, 1020–1026.

  • Bergsagel PL, Chesi M, Nardini E, Brents LA, Kirby SL and Kuehl WM . (1996). Proc. Natl. Acad. Sci. USA, 93, 13931–13936.

  • Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X, Chopin D, Thiery JP and Radvanyi F . (1999). Nat. Genet., 23, 18–20.

  • Cavo M, Terragna C, Martinelli G, Ronconi S, Zamagni E, Tosi P, Lemoli RM, Benni M, Pagliani G, Bandini G and Tura S . (2000). Blood, 96, 355–357.

  • Chen J, DeAngelo DJ, Kutok JL, Williams IR, Lee BH, Wadleigh M, Duclos N, Cohen S, Adelsperger J, Okabe R, Coburn A, Galinsky I, Huntly B, Cohen P, Meyer T, Fabbro D, Banerji L, Griffin JD, Xiao S, Fletcher JA, Stone RM and Gilliland DG . (2004a). Proc. Natl. Acad. Sci. USA, 101, 14479–14484.

  • Chen J, Williams IR, Kutok JL, Duclos N, Anastasiadou E, Masters SC, Fu H and Gilliland DG . (2004b). Blood, 104, 535–542.

  • Chen J, Williams IR, Lee BH, Duclos N, Huntly B, Donoghue DJ and Gilliland DG . (2005). Blood, 106, 328–337.

  • Chesi M, Bergsagel PL, Brents LA, Smith CM, Gerhard DS and Kuehl WM . (1996). Blood, 88, 674–681.

  • Chesi M, Bergsagel PL, Shonukan OO, Martelli ML, Brents LA, Chen T, Schrock E, Ried T and Kuehl WM . (1998a). Blood, 91, 4457–4463.

  • Chesi M, Brents LA, Ely SA, Bais C, Robbiani DF, Mesri EA, Kuehl WM and Bergsagel PL . (2001). Blood, 97, 729–736.

  • Chesi M, Nardini E, Brents LA, Schrock E, Ried T, Kuehl WM and Bergsagel PL . (1997). Nat. Genet., 16, 260–264.

  • Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM and Bergsagel PL . (1998b). Blood, 92, 3025–3034.

  • Colvin JS, Bohne BA, Harding GW, McEwen DG and Ornitz DM . (1996). Nat. Genet., 12, 390–397.

  • Cools J, Stover EH, Boulton CL, Gotlib J, Legare RD, Amaral SM, Curley DP, Duclos N, Rowan R, Kutok JL, Lee BH, Williams IR, Coutre SE, Stone RM, DeAngelo DJ, Marynen P, Manley PW, Meyer T, Fabbro D, Neuberg D, Weisberg E, Griffin JD and Gilliland DG . (2003). Cancer Cell, 3, 459–469.

  • Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD and Joensuu H . (2002). N. Engl. J. Med., 347, 472–480.

  • Druker BJ . (2003). Semin. Hematol., 40, 50–58.

  • Estey EH, Fisher T, Giles F, Feldman EJ, Ehninger G, Schiller GJ, Klimek VM, Nimer SD, De Angelo DJ, Gilliland DG, Fox E, Wang YF, Rosamilia M, Resta D, Chen P and Stone RM . (2003). Blood, 102, 614a.

  • Fabbro D, Ruetz S, Bodis S, Pruschy M, Csermak K, Man A, Campochiaro P, Wood J, O'Reilly T and Meyer T . (2000). Anticancer Drug Des., 15, 17–28.

  • Golla A, Lichmer P, von Gernet S, Winterpacht A, Fairley J, Murken J and Schuffenhauer S . (1997). J. Med. Genet., 34, 683–684.

  • Golub TR, McLean T, Stegmaier K, Carroll M, Tomasson M and Gilliland DG . (1996). Biochim. Biophys. Acta, 1288, M7–M10.

  • Grand EK, Chase AJ, Heath C, Rahemtulla A and Cross NC . (2004). Leukemia, 18, 962–966.

  • Heffner Jr LT and Lonial S . (2003). Drugs, 63, 1621–1636.

  • Keats JJ, Maxwell CA, Taylor BJ, Hendzel MJ, Chesi M, Bergsagel PL, Larratt LM, Mant MJ, Reiman T, Belch AR and Pilarski LM . (2005). Blood, 105, 4060–4069.

  • Kelly LM, Yu JC, Boulton CL, Apatira M, Li J, Sullivan CM, Williams I, Amaral SM, Curley DP, Duclos N, Neuberg D, Scarborough RM, Pandey A, Hollenbach S, Abe K, Lokker NA, Gilliland DG and Giese NA . (2002). Cancer Cell, 1, 421–432.

  • Lemoli RM, Martinelli G, Zamagni E, Motta MR, Rizzi S, Terragna C, Rondelli R, Ronconi S, Curti A, Bonifazi F, Tura S and Cavo M . (2000). Blood, 95, 2234–2239.

  • Li Z, Zhu YX, Plowright EE, Bergsagel PL, Chesi M, Patterson B, Hawley TS, Hawley RG and Stewart AK . (2001). Blood, 97, 2413–2419.

  • Liu Q, Schwaller J, Kutok J, Cain D, Aster JC, Williams IR and Gilliland DG . (2000). EMBO J., 19, 1827–1838.

  • Martinelli G, Terragna C, Zamagni E, Ronconi S, Tosi P, Lemoli RM, Bandini G, Motta MR, Testoni N, Amabile M, Ottaviani E, Vianelli N, de Vivo A, Gozzetti A, Tura S and Cavo M . (2000). J. Clin. Oncol., 18, 2273–2281.

  • Naski MC, Wang Q, Xu J and Ornitz DM . (1996). Nat. Genet., 13, 233–237.

  • Paramore A and Frantz S . (2003). Nat. Rev. Drug Discov., 2, 611–612.

  • Paterson JL, Li Z, Wen XY, Masih-Khan E, Chang H, Pollett JB, Trudel S and Stewart AK . (2004). Br. J. Haematol., 124, 595–603.

  • Persons DA, Allay JA, Allay ER, Smeyne RJ, Ashmun RA, Sorrentino BP and Nienhuis AW . (1997). Blood, 90, 1777–1786.

  • Plowright EE, Li Z, Bergsagel PL, Chesi M, Barber DL, Branch DR, Hawley RG and Stewart AK . (2000). Blood, 95, 992–998.

  • Richardson P, Hideshima T and Anderson K . (2002). Biomed. Pharmacother., 56, 115–128.

  • Ronchetti D, Greco A, Compasso S, Colombo G, Dell'Era P, Otsuki T, Lombardi L and Neri A . (2001). Oncogene, 20, 3553–3562.

  • San Miguel JF, Blade Creixenti J and Garcia-Sanz R . (1999). Haematologica, 84, 36–58.

  • Santra M, Zhan F, Tian E, Barlogie B and Shaughnessy Jr J . (2003). Blood, 101, 2374–2376.

  • Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS, Peeters P, Van Rompaey L, Van Etten RA, Ilaria Jr R, Marynen P and Gilliland DG . (1998). EMBO J., 17, 5321–5333.

  • Sternberg DW, Tomasson MH, Carroll M, Curley DP, Barker G, Caprio M, Wilbanks A, Kazlauskas A and Gilliland DG . (2001). Blood, 98, 3390–3397.

  • Stone RM, Klimek V, DeAngelo DJ, Nimer S, Estey E, Galinsky I, Neuberg D, Yap A, Fox EA, Gilliland DG and Griffin J . (2003). Blood, 100, 86a.

  • Tavormina PL, Shiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH and Wasmuth JJ . (1995). Nat. Genet., 9, 321–328.

  • Trudel S, Ely S, Farooqi Y, Affer M, Robbiani DF, Chesi M and Bergsagel PL . (2004). Blood, 103, 3521–3528.

  • Webster MK and Donoghue DJ . (1996). EMBO J., 15, 520–527.

  • Weisberg E, Boulton C, Kelly LM, Manley P, Fabbro D, Meyer T, Gilliland DG and Griffin JD . (2002). Cancer Cell, 1, 433–443.

  • Yagasaki F, Wakao D, Yokoyama Y, Uchida Y, Murohashi I, Kayano H, Taniwaki M, Matsuda A and Bessho M . (2001). Cancer Res., 61, 8371–8374.

Download references

Acknowledgements

We gratefully acknowledge administrative assistance from Alexis Bywater and valuable discussion with members of the Gilliland laboratory. We thank Dr Takemi Otsuki at Kawasaki Medical School, Japan, for kindly providing KMS11 cells. This work was supported in part by NIH grants DK50654, CA66996 and the Leukemia and Lymphoma Society (DGG), the Career Development Award of the NCI SPORE Grant for Multiple Myeloma (CSM), NIH grants RO-1 50947 and PO-1 78378 (KCA). JC is a Fellow and CSM is a Special Fellow of the Leukemia and Lymphoma Society. KCA and DGG are Doris Duke Distinguished Clinical Research Scientists and DGG is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dwight Gary Gilliland.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, J., Lee, B., Williams, I. et al. FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies. Oncogene 24, 8259–8267 (2005). https://doi.org/10.1038/sj.onc.1208989

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208989

Keywords

This article is cited by

Search

Quick links