Bortezomib therapeutic effect is associated with expression and mutation of FGFR3 in human lymphoma cells.

OBJECTIVE

Ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) has been observed in many malignant cancer patients, including those with lymphoma. This study investigated whether the therapeutic effect of bortezomib in lymphoma is associated with FGFR3-expression.

MATERIALS AND

METHODS

Cell proliferation and apoptosis assays were performed in minimal FGFR3 expressing U937 cells and compared to U937 cells overexpressing FGFR3 wild-type, or Y373C or K650E mutant FGFR3.

RESULTS

Results from this study suggested the expression of FGFR3 protein is associated with the therapeutic effect of bortezomib. It was observed that bortezomib-induced apoptotic death is correlated with FGFR3 expression. U937 cells overexpression of wild-type FGFR3 demonstrated resistance to bortezomib treatment. U937 cells expressing Y373C mutated FGFR3 showed an almost equal resistance to bortezomib as U937 cells expressing wild-type FGFR3. U937 cells expressing mutated K650E FGFR3 showed more sensitivity to bortezomib than did the parental U937 cells. Furthermore, increased expression of Mcl-1 and decreased expression of NF-kappaB p65 suggested that bortezomib resistance associated with Y373C mutation and wild-type FGFR3 may be partly mediated through Bcl-2 and NF-kappaB signaling.

CONCLUSION

Data from this study indicate that mutation status and the expression level of FGFR3 may be associated with bortezomib-related treatment resistance in lymphoma.