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Comparative pre-clinical evaluation of receptor tyrosine kinase inhibitors for the treatment of multiple myeloma

Lookup NU author(s): Michael Batey, Dr Yan Zhao, Dr Helen Maitland, Professor Hing Leung, Dr Andrew Hall, Professor Graham Jackson, Professor Herbie Newell, Professor Julie Irving

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Abstract

Background: Fibroblast growth factor receptor 3 (FGFR3) is up-regulated as a result of the t(4;14)(p16;q32) translocation that occurs in up to 20% of multiple myeloma (MM) patients. Recent studies have demonstrated that up-regulation of FGFR3 promotes cell survival, growth and drug resistance in malignant plasma cells, both in vitro and in vivo. Therefore, inhibition of FGFR3 signalling is potential target for the chemotherapeutic intervention in t(4; 14) MM. Methods: Small molecule receptor tyrosine kinase inhibitors (PD173074, sunitinib (SU-11248), vandetanib (ZD6474) and vatalanib (PTK-787)) with varying degrees of inhibitory activity and selectivity against FGFR, were assessed in Ba/f3 cells expressing ZNF198-FGFR1 and MM cell lines. Cell viability, FGFR3 and ZNF198-FGFR1 phosphorylation and apoptosis were evaluated by growth inhibition assays, immunoblotting and fluorescence-activated cell sorting analysis, respectively. An in vivo study was performed with sunitinib in t(4; 14)-positive and t(4; 14)-negative human MM tumour xenograft models. Results: PD173074 and sunitinib differentially inhibited the growth of Ba/f3 cells expressing ZNF198-FGFR1 (GI(50) = 10 nM and 730 nM, versus GI50 > 1 mu M and 2.7 mu M for parental cells; p < 0.0001) and t(4; 14) positive MM cell lines (GI50 = 4-10 mu M and 1-3 mu M, versus GI50 = 14-15 mu M and 4-5 mu M for t(4; 14) negative MM cells; p <= 0.002). In addition, both PD173074 and sunitinib inhibited the activation of FGFR3 in t(4; 14)-positive MM cells. PD173074 and sunitinib induced an apoptotic response in a concentration and time-dependent manner in a t(4; 14)-positive (PD174073 and sunitinib) but not a t(4; 14)-negative MM cell line (sunitinib only); however, in in vivo tumours derived from the same cell lines, sunitinib was only active in the t(4; 14)-negative model. Conclusions: These data demonstrate that PD173074 and sunitinib are inhibitors of FGFR3 in MM cell lines, and that sunitinib has in vivo activity in a human MM tumour xenograft model. However, caution should be exercised in using the t(4; 14) translocation as a predictive biomarker for patient selection in clinical trials with sunitinib. (C) 2011 Elsevier Ltd. All rights reserved.

Publication metadata

Author(s): de Brito LR, Batey MA, Zhao Y, Squires MS, Maitland H, Leung HY, Hall AG, Jackson G, Newell DR, Irving JAE

Publication type: Article

Publication status: Published

Journal: Leukemia Research

Year: 2011

Volume: 35

Issue: 9

Pages: 1233-1240

Print publication date: 11/02/2011

ISSN (print): 0145-2126

ISSN (electronic): 1873-5835

Publisher: Pergamon

URL: http://dx.doi.org/10.1016/j.leukres.2011.01.011

DOI: 10.1016/j.leukres.2011.01.011

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