Fibroblast Growth Factor Receptor 3 (FGFR3) Associated with the CD20 Antigen Regulates the Rituximab-induced Proliferation Inhibition in B-cell Lymphoma Cells

Rituximab is reported to inhibit the proliferation of lymphoma cells through an unknown CD20-mediated signal transduction pathway. Herein, we investigated cell surface molecules involved in the CD20-mediated signal transduction pathway by using a recently developed technique named enzyme-mediated activation of radical sources. Using this method, we found that under stimulation with rituximab and another anti-CD20 antibody B-Ly1, CD20 was physically associated with fibroblast growth factor receptor 3 (FGFR3) as well as some other receptor tyrosine kinases in Raji cells. However, under stimulation with a noncytotoxic anti-CD20 antibody 2H7, CD20 was not associated with FGFR3 but with the PDGF receptor β. When the tyrosine kinase activity of FGFR3 was inhibited by the chemical inhibitor PD173074 or an siRNA knockdown strategy, the proliferation inhibition by rituximab was attenuated, indicating that FGFR3 participates in the rituximab-dependent signal transduction pathway leading to proliferation inhibition. These observations raise the possibility that concomitant targeted therapy toward FGFR3 might improve the efficacy and safety of the rituximab therapy. Background: The mechanism of cytotoxicity by rituximab treatment remains to be elucidated. Results: FGFR3 was physically associated with CD20 under stimulation with rituximab, and it affected the cytotoxicity. Conclusion: FGFR3 participates in the rituximab-induced proliferation inhibition in B-cell lymphoma cells. Significance: Identification of the signal molecules associated with the therapeutic antibody complex is useful for finding the target molecules for concomitant therapy.