B-cell non-Hodgkin lymphomas (B-NHL) are a heterogeneous group of malignancies arising from peripheral B-lymphocytes. Among them, a subset of Diffuse Large B-cell Lymphomas (DLBCL) and all Burkitt’s lymphomas (BL) are c-MYC-driven aggressive B-NHL. Although current treatments often provide complete remission, approximately half of the patients relapse. Recently we have demonstrated that activation of the fibroblast growth factor (FGF) signaling is involved in the stabilization of c-MYC protein in different tumor types, FGF or FGF receptor (FGFR) inhibition leading to the proteasomal degradation of c-MYC protein. Thus, FGF/FGFR blockade may represent a promising therapeutic strategy for aggressive B-NHL. The aim of this study is to investigate the effects of FGF signaling inhibition in c-MYC-driven aggressive B-NHL by using two different approaches: (i) an extracellular FGF trapping strategy and (ii) a FGFR TK inhibition approach.

FGFs and FGFRs expression were assessed by qPCR. FGFR activation and c-MYC protein levels were assessed by western blot and immunohistochemical analyses. The effects of FGF/FGFR inhibitors were investigated by viable cell counting, TMRE, Mitosox and Annexin-V/PI staining and cytofluorimetric analyses. In vivo experiments were performed in NOD/SCID mice.

c-MYC positive DLBCL and BL patient-derived samples express high levels of activated/phosphorylated (p)FGFR. Interestingly, FGFR phosphorylation was not observed in c-MYC negative DLBCL samples, suggesting a strong correlation between FGFR activation and c-MYC protein expression. To assess the role of the FGF/FGFR system in c-MYC-driven B-NHL, we tested the effect on lymphoma fitness of the FGF trap molecule NSC12 and the FDA-approved FGFR TK inhibitor Erdafitinib in c-MYC positive DLBCL (RI-1, U2932, SU-DHL-6 and SU-DHL-10) and BL (RAJI, DAUDI) cell lines. All cell lines express several FGFRs and FGF ligands and high levels of pFGFR in the absence of exogenous stimuli, indicating the presence of an autocrine FGF stimulation. In vitro NSC12 or Erdafitinib treatments strongly inhibited FGFR activation and induced the rapid proteasomal degradation of c-MYC protein. This was confirmed by co-treatment with the proteosome inhibitor MG132 that prevented c-MYC degradation. The decrease of c-MYC protein levels was paralleled by reduced tumor cell proliferation and increased ROS-mediated apoptosis in all cell lines tested. To note, NSC12 or Erdafitinib in combination with the standard therapy R-CHOP exerted synergistic anti-lymphoma effects. In vivo treatment with NSC12 or Erdafitinib significantly reduced the growth of both DLBCL and BL tumor xenografts.

These findings demonstrate that the FGF/FGFR system sustains the growth and survival of DLBCL and BL cells and open new therapeutic hints for the treatment of c-MYC-driven aggressive B-NHL.

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