FGFR3 Is Overexpressed Waldenström Macroglobulinemia and Its Inhibition by Dovitinib Induces Apoptosis and Overcomes Stroma-Induced Proliferation

Abstract

Purpose: There is no standard of therapy for the treatment of Waldenstr€ om macroglobulinemia (WM), therefore there is a need for the development of new agents. Fibroblast growth factor receptor 3 (FGFR3) was shown to play a major role in several types in cancer. Dovitinib, an inhibitor of FGFR3, was effective in hematologic malignancies. In this study, we tested FGFR3 as a therapeutic target in WM and tested the effect of dovitinib on cell proliferation and apoptosis of WM cells in the context of BM microenvironment.Methods: The expression of FGFR3 in WM cells was tested using immunofluorescence and flow cytometry. Cell signaling in response to stimulation with FGF3 and stromal cells, and its inhibition by dovitinib was performed using immunoblotting. Cell survival and cell proliferation were assessed by MTT and BrdU assays. Apoptosis was measured by detection of APO-2.7 and cleavage of caspase-3 using flow cytometry. Cell cycle was performed by PI staining of cells and flow cytometry. The combinatory effect of dovitinib with other drugs was analyzed using Calcusyn software. The effect of dovitinib was tested in vivo.Results: FGFR3 was overexpressed in WM cells and its activation induced cell proliferation. Inhibition of FGFR3 with dovitinib decreased cell survival, increased apoptosis, and induced cell cycle arrest. Inhibition of FGFR3 by dovitinib reduced the interaction of WM to bone marrow components, and reversed its proliferative effect. Dovitinib had an additive effect with other drugs. Moreover, dovitinib reduced WM tumor progression in vivo.Conclusion: We report that FGFR3 is a novel therapeutic target in WM, and suggest dovitinib for future clinical trial the treatment of patients with WM. Clin Cancer Res; 17(13); 4389-99. Ó2011 AACR.

Eph-B2/Ephrin-B2 Interaction Plays a Major Role in the Adhesion and Proliferation of Waldenstrom's Macroglobulinemia

“…To determine early differences in tumor growth patterns and to confirm that the cells did not loose siRNA inhibition, the mice were sacrificed after 1 week (21,22 (50-1,000 ng/mL) on SDF1-induced chemotaxis of BCWM1 cells. B, the effect of recombinant ephrin-B2 (50-1,000 ng/mL) on chemotaxis of BCWM1 cells using an 8-micron pore filters for transwell migration assay.…”

Hypoxia Promotes Dissemination and Colonization in New Bone Marrow Niches in Waldenström Macroglobulinemia

“…Effect of tumor progression on hypoxia in Waldenstr€ om macroglobulinemia bone marrow BCWM.1 cells were genetically engineered to express mCherry fluorescent protein and luciferase (Luc), as described previously (5). Human BCWM.1-mCherry cells were injected into 12 SCID mice intravenously at different concentrations of 0.5 Â 10 6 , 1 Â 10 6 , and 2.5 Â 10 6 cells per mouse (4 mice per condition) and allowed to grow for 3 weeks.…”

“…The Waldenstr€ om macroglobulinemia cells infiltrate specifically into the bone marrow niche which implies the critical role of the bone marrow as a supportive microenvironment for the Waldenstr€ om macroglobulinemia cells due to the various interactions (2)(3)(4). We have previously shown in Waldenstr€ om macroglobulinemia that the bone marrow milieu promotes tumor progression including cell proliferation, survival, and drug resistance through production of cytokines, regulation of cell interaction, cell adhesion with stroma and endothelial cells, and cell trafficking (3,(5)(6)(7). We have also shown before that the bone marrow microenvironment plays a crucial role in the progression and drug resistance of other hematologic malignancies including multiple myeloma (8)(9)(10) and chronic myeloid leukemia (CML; refs.…”

Axl activates fibroblast growth factor receptor pathway to potentiate survival signals in B-cell chronic lymphocytic leukemia cells

“…2I ). Recently, overexpression of FGFR3 has been reported in Waldenstrom macroglobulinemia (WM) and that inhibition of FGFR3 induces apoptosis in WM cells and overcomes stromal protection 14 . Of interest, we also found that while in vitro combined treatment of CLL B-cells with TKI-258 and ibrutinib produced synergistic effects in 5 of 7 cases ( Fig.…”