Trudel Suzanne, Ely Scott, Farooqi Yildiz, Affer Maurizio, Robbiani Davide F, Chesi Marta, Bergsagel P Leif
Department of Medicine, Weill Medical College and Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA.
Blood. 2004 May 1;103(9):3521-8. doi: 10.1182/blood-2003-10-3650. Epub 2004 Jan 8.
We have previously shown that dysregulation of fibroblast growth factor receptor 3 (FGFR3) by the t(4;14) translocation is a primary event in multiple myeloma (MM) and that activating mutations of FGFR3 are acquired in some cases. We describe here inhibition of wild-type (WT) and constitutively activated mutant FGFR3 autophosphorylation by the small molecule inhibitor, PD173074. Inhibition of FGFR3 in human myeloma cell lines was associated with decreased viability and tumor cell growth arrest. Further, morphologic, phenotypic, and functional changes typical of plasma cell (PC) differentiation, including increase in light-chain secretion and expression of CD31, were observed and this was followed by apoptosis. Finally, using a mouse model of FGFR3 myeloma, we demonstrate a delay in tumor progression and prolonged survival of mice treated with PD173074. These results indicate that inhibition of FGFR3, even in advanced disease associated with multiple genetic changes, may allow the cell to complete its developmental program and render it sensitive to apoptotic signals. In addition, this represents the validation of a therapeutic target in MM that may benefit patients who have a very poor prognosis with currently available treatments.
我们之前已经表明，t(4;14)易位导致的成纤维细胞生长因子受体3（FGFR3）失调是多发性骨髓瘤（MM）中的一个主要事件，并且在某些情况下会出现FGFR3的激活突变。我们在此描述了小分子抑制剂PD173074对野生型（WT）和组成型激活突变体FGFR3自身磷酸化的抑制作用。在人骨髓瘤细胞系中抑制FGFR3与细胞活力降低和肿瘤细胞生长停滞相关。此外，观察到了浆细胞（PC）分化典型的形态、表型和功能变化，包括轻链分泌增加和CD31表达，随后发生凋亡。最后，使用FGFR3骨髓瘤小鼠模型，我们证明了用PD173074治疗的小鼠肿瘤进展延迟且生存期延长。这些结果表明，即使在与多种基因变化相关的晚期疾病中，抑制FGFR3也可能使细胞完成其发育程序并使其对凋亡信号敏感。此外，这代表了MM中一个治疗靶点的验证，可能使目前可用治疗预后很差的患者受益。
