Analysis of weak points in oncogenic tyrosine kinase-dependent growth

在多发性骨髓瘤（MM）患者中检测到异位表达的成纤维细胞生长因子受体3 （FGFR3）及其构成性活性突变。本研究调查了硼替佐米对恶性浆细胞的细胞毒性作用是否与FGFR3表达和FGFR3突变的存在有关。材料和方法：在浆细胞瘤细胞系、FR4细胞和骨髓瘤细胞系、过表达野生型FGFR3 （FGFR3WT）或两种不同突变体FGFR3K650E或FGFR3Y373C的RPMI8226细胞中进行细胞凋亡实验，并比较每种细胞对内质网（ER）应激蛋白的诱导。结果：与含有mock、FGFR3WT或FGFR3Y373C的FR4细胞相比，含有FGFR3K650E的FR4细胞对bortezomib的敏感性增强，内质网应激蛋白的诱导增加。FGFR3K650E的RPMI8226细胞也显示出增强的硼替佐米敏感性。结论：本研究表明FGFR3K650E通过内质网应激途径与恶性浆细胞的硼替佐米敏感性相关。

The ectopically expressed fibroblast growth factor receptor 3 (FGFR3) and its constitutive 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 andthe 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 (FGFR3WT) or two different mutants, FGFR3K650E or FGFR3Y373C, and the induction of endoplasmic reticulum (ER) stress protein was compared between each type of cells. Results: FR4 cells with FGFR3K650E showed enhanced sensitivity to bortezomib together with increased induction of ER stress proteins, compared to FR4 cells with mock, FGFR3WT or FGFR3Y373C. RPMI8226 cells with FGFR3K650E also showed enhanced bortezomib sensitivity. Conclusion: This study indicated that FGFR3K650E is associated with bortezomib sensitivity in malignant plasma cells via ER stress pathways.