Bortezomib, Dexamethasone, and Fibroblast Growth Factor Receptor 3-Specific Tyrosine Kinase Inhibitor in t(4;14) Myeloma
Bortezomib, Dexamethasone, and Fibroblast Growth Factor Receptor 3-Specific Tyrosine Kinase Inhibitor in t(4;14) Myeloma
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DOI：
10.1158/1078-0432.ccr-08-1612
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发表时间：
2009-01-15
影响因子：
11.5
通讯作者：
Kienast, Joachim
中科院分区：
文献类型：
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作者：
Bisping, Guido;Wenning, Doris;Kienast, Joachim
目的：新型药物（包括靶向方法）改变了多发性骨髓瘤（MM）的治疗模式，也可能对预后不良的t（4;14）亚组具有治疗潜力; t（4;14）导致过度表达和活化的成纤维细胞生长因子受体3（FGFR 3）。阻断该受体酪氨酸激酶（RTK）可诱导t（4;14）+ MM细胞凋亡，并降低与骨髓基质细胞（BMSC）的粘附。使用新型药物的组合，我们研究了肿瘤细胞内单一药物活性的潜在增强、骨髓微环境的靶向或t（4;14）+ MM中耐药性的规避。14）+ MM子集，应用包括FGFR 3酪氨酸激酶抑制剂（RTKI）、蛋白酶体抑制剂硼替佐米和地塞米松的药物组合。RTKI、硼替佐米和地塞米松作为单一药物在t（4;14）+MM中是有活性的。Mcl-1的减少，p44/42促分裂原活化蛋白激酶的下调，以及促凋亡应激活化蛋白/c-Jun NH 2-末端激酶的活化）。通过RTKI与地塞米松或硼替佐米的组合发现了协同或累加效应。在选定的t（4;14）+ MM病例中，三联治疗上级双联治疗。骨髓基质细胞或外源性白细胞介素-6对MM细胞凋亡的预防作用被药物组合所规避。在t（4;14）+，N-ras突变的NCI-H929细胞中，通过添加地塞米松克服了对RTKI的抗性。值得注意的是，RTKI和地塞米松的组合在硼替佐米不敏感的t（4;14）+ MM中显示出附加的促凋亡作用。结论：在预后不良的t（4;14）+ MM中联合使用新药应至少考虑硼替佐米的敏感性和可能的Ras突变状态。
Purpose: Novel drugs including targeted approaches have changed treatment paradigms for multiple myeloma (MM) and may also have therapeutic potential in the poor-prognosis t(4;14) subset; t(4;14) results in overexpressed and activated fibroblast growth factor receptor 3 (FGFR3). Blocking this receptor tyrosine kinase (RTK) induces apoptosis in t(4;14)+ MM cells and decreases adhesion to bone marrow stromal cells (BMSC). Using combinations of novel drugs, we investigated potential enhancement of single-agent activities within the tumor cells, targeting of the marrow micromilieu, or circumvention of drug resistance in t(4;14)+ MM.Experimental Design: We tested effects on apoptosis and related signaling pathways in the t(4;14)+ MM subset, applying drug combinations including a FGFR3 tyrosine kinase inhibitor (RTKI), the proteasome inhibitor bortezomib, and dexamethasone.Results: RTKI, bortezomib, and dexamethasone were active as single agents in t(4;14)+ MM. RTK inhibition triggered complementary proapoptotic pathways (e.g., decrease of Mcl-1, downregulation of p44/42 mitogen-activated protein kinase, and activation of proapoptotic stress-activated protein/c-Jun NH2-terminal kinases). Synergistic or additive effects were found by combinations of RTKI with dexamethasone or bortezomib. In selected cases of t(4;14)+ MM, triple combinations were superior to dual combinations tested. Prevention from MM cell apoptosis by BMSC or exogenous interleukin-6 was circumvented by drug combinations. In t(4;14)+, N-ras - mutated NCI-H929 cells, resistance to RTKI was overcome by addition of dexamethasone. Notably, the combination of RTKI and dexamethasone showed additive proapoptotic effects in bortezomib-insensitive t(4;14) + MM.Conclusions: Combining novel drugs in poor-prognosis t(4;14)+ MM should take into account at least bortezomib sensitivity and probably Ras mutational status.