The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling.
The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling.
复制标题
DOI：
10.3324/haematol.2017.164632
复制
发表时间：
2017-10
期刊：
影响因子：
10.1
通讯作者：
de Larrea CF
中科院分区：
文献类型：
--
作者：
Díaz T;Rodríguez V;Lozano E;Mena MP;Calderón M;Rosiñol L;Martínez A;Tovar N;Pérez-Galán P;Bladé J;Roué G;de Larrea CF
大多数接受当前治疗（包括免疫调节药物）的多发性骨髓瘤患者最终会出现复发/难治性疾病。来那度胺的临床活性依赖于Ikaros的降解和随后IRF 4表达的降低，这两者都是骨髓瘤细胞存活所需的，并参与MYC转录的调节。因此，我们试图确定MYC干扰疗法与来那度胺/地塞米松的联合作用。我们分析了BET布罗莫结构域抑制剂CPI 203与来那度胺/地塞米松方案组合在骨髓瘤细胞系中的潜在治疗效果。CPI 203在细胞系中表现出剂量依赖性的细胞生长抑制作用，实际上在来那度胺/地塞米松耐药细胞中也是如此（0.5 μM时的中位反应：65.4%），其特征在于G1细胞周期阻滞以及MYC和Ikaros信号传导的伴随抑制。这些作用通过添加来那度胺/地塞米松而增强。在与间充质基质细胞系stromaNKtert共培养的多发性骨髓瘤患者的原代浆细胞中验证了结果。一致地，药物组合引起细胞增殖减少50%，并且与基础Ikaros mRNA表达水平相关（P=0.04）。最后，在骨髓瘤的SCID小鼠异种移植模型中，向来那度胺/地塞米松中添加CPI 203降低了肿瘤负荷，这通过较低的葡萄糖摄取和生长停滞标志物GADD 45 B的增加来证明，同时下调了关键转录因子如MYC、Ikaros和IRF 4。综上所述，我们的数据表明，BET布罗莫结构域抑制剂与基于来那度胺的方案的组合可能代表改善复发性/难治性多发性骨髓瘤患者的应答的治疗方法，即使在先前对免疫调节药物的应答不佳的情况下。
Most patients with multiple myeloma treated with current therapies, including immunomodulatory drugs, eventually develop relapsed/refractory disease. Clinical activity of lenalidomide relies on degradation of Ikaros and the consequent reduction in IRF4 expression, both required for myeloma cell survival and involved in the regulation of MYC transcription. Thus, we sought to determine the combinational effect of an MYC-interfering therapy with lenalidomide/dexamethasone. We analyzed the potential therapeutic effect of the combination of the BET bromodomain inhibitor CPI203 with the lenalidomide/dexamethasone regimen in myeloma cell lines. CPI203 exerted a dose-dependent cell growth inhibition in cell lines, indeed in lenalidomide/dexamethasone-resistant cells (median response at 0.5 μM: 65.4%), characterized by G1 cell cycle blockade and a concomitant inhibition of MYC and Ikaros signaling. These effects were potentiated by the addition of lenalidomide/dexamethasone. Results were validated in primary plasma cells from patients with multiple myeloma co-cultured with the mesenchymal stromal cell line stromaNKtert. Consistently, the drug combination evoked a 50% reduction in cell proliferation and correlated with basal Ikaros mRNA expression levels (P=0.04). Finally, in a SCID mouse xenotransplant model of myeloma, addition of CPI203 to lenalidomide/dexamethasone decreased tumor burden, evidenced by a lower glucose uptake and increase in the growth arrest marker GADD45B, with simultaneous downregulation of key transcription factors such as MYC, Ikaros and IRF4. Taken together, our data show that the combination of a BET bromodomain inhibitor with a lenalidomide-based regimen may represent a therapeutic approach to improve the response in relapsed/refractory patients with multiple myeloma, even in cases with suboptimal prior response to immunomodulatory drugs.