Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma
Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma
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DOI：
10.1182/blood-2003-10-3650
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发表时间：
2004-05-01
期刊：
影响因子：
20.3
通讯作者：
Bergsagel, PL
中科院分区：
文献类型：
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作者：
Trudel, S;Ely, S;Bergsagel, PL
我们以前已经证明，t（4;14）易位引起的成纤维细胞生长因子受体3（FGFR 3）失调是多发性骨髓瘤（MM）的主要事件，并且在某些情况下获得了FGFR 3的激活突变。我们在此描述了小分子抑制剂PD 173074对野生型（WT）和组成型激活突变体FGFR 3自磷酸化的抑制作用。人骨髓瘤细胞系中FGFR 3的抑制与活力降低和肿瘤细胞生长停滞相关。此外，观察到浆细胞（PC）分化的典型形态、表型和功能变化，包括轻链分泌和CD 31表达增加，随后是细胞凋亡。最后，使用FGFR 3骨髓瘤小鼠模型，我们证明了用PD 173074治疗的小鼠的肿瘤进展延迟和存活期延长。这些结果表明，即使在与多种遗传变化相关的晚期疾病中，FGFR 3的抑制也可以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治疗靶点的验证，可能使目前可用治疗的预后非常差的患者受益。(C)2004年，美国血液学会。
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 de-creased 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. (C) 2004 by The American Society of Hematology.