Constitutively active FGFR3 with Lys650Glu mutation enhances bortezomib sensitivity in plasma cell malignancy.

The ectopically expressed fibroblast growth factor receptor 3 (FGFR3) and its constitutively active mutations have been detected in patients with multiple myeloma (MM). This study investigated whether the cytotoxic effects of bortezomib on malignant plasma cells are associated with FGFR3 expression and the existence of mutations of FGFR3. Materials and Methods: Cell apoptosis assays were performed in a plasmacytoma cell line, FR4 cells and a myeloma cell line, RPMI8226 cells overexpressing wild-type FGFR3 (FGFR3(WT)) or two different mutants, FGFR3(K650E) or FGFR3(Y373C), and the induction of endoplasmic reticulum (ER) stress protein was compared between each type of cell. Results: FR4 cells with FGFR3(K650E) showed enhanced sensitivity to bortezomib together with increased induction of ER stress proteins, compared to FR4 cells with mock, FGFR3(WT) or FGFR3(Y373C) RPMI8226 cells with FGFR3(K650E) also showed enhanced bortezomib sensitivity. Conclusion: This study indicated that FGFR3K650E is associated with bortezomib sensitivity in malignant plasma cells via ER stress pathways.