Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma.
Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma.
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DOI：
10.18632/oncotarget.4214
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发表时间：
2015-08-07
期刊：
影响因子：
--
通讯作者：
Tyner JW
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文献类型：
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作者：
Siegel MB;Liu SQ;Davare MA;Spurgeon SE;Loriaux MM;Druker BJ;Scott EC;Tyner JW
尽管多发性骨髓瘤的治疗取得了重大进展，但耐药性是不可避免的，需要新的治疗方法。我们的目的是确定新的，有效的小分子组合用于耐药多发性骨髓瘤。使用一组116种小分子抑制剂筛选潜在治疗靶点的耐药骨髓瘤细胞系。进一步联合研究发现在硼替佐米或美法仑抗性骨髓瘤细胞系中具有增强活性的药剂。在原代患者细胞中评价感兴趣的协同组合。美法仑和硼替佐米抗性细胞之间的总体单药剂药物敏感性概况显著不同，然而，观察到溴结构域抑制剂CPI 203与其野生型对应物相比在硼替佐米和美法仑抗性细胞系中具有增强的活性。发现硼替佐米和CPI 203的组合在硼替佐米和美法仑抗性细胞系以及来自最近蛋白酶体抑制剂治疗难治的患者的原发性多发性骨髓瘤样品中具有协同作用。CPI 203-硼替佐米组合导致增强的细胞凋亡和抗增殖作用。最后，与先前关于硼替佐米和其他表观遗传修饰剂之间协同作用的报道（其涉及MYC下调或NOXA诱导）相反，我们的分析表明，CPI 203-硼替佐米协同作用与这些事件无关。我们的临床前数据支持溴结构域抑制剂CPI 203与硼替佐米或烷化剂联合治疗耐药多发性骨髓瘤的临床研究。
Despite significant therapeutic progress in multiple myeloma, drug resistance is uniformly inevitable and new treatments are needed. Our aim was to identify novel, efficacious small-molecule combinations for use in drug resistant multiple myeloma. A panel of 116 small molecule inhibitors was used to screen resistant myeloma cell lines for potential therapeutic targets. Agents found to have enhanced activity in the bortezomib or melphalan resistant myeloma cell lines were investigated further in combination. Synergistic combinations of interest were evaluated in primary patient cells. The overall single-agent drug sensitivity profiles were dramatically different between melphalan and bortezomib resistant cells, however, the bromodomain inhibitor, CPI203, was observed to have enhanced activity in both the bortezomib and melphalan resistant lines compared to their wild-type counterparts. The combination of bortezomib and CPI203 was found to be synergistic in both the bortezomib and melphalan resistant cell lines as well as in a primary multiple myeloma sample from a patient refractory to recent proteasome inhibitor treatment. The CPI203-bortezomib combination led to enhanced apoptosis and anti-proliferative effects. Finally, in contrast to prior reports of synergy between bortezomib and other epigenetic modifying agents, which implicated MYC downregulation or NOXA induction, our analyses suggest that CPI203-bortezomib synergy is independent of these events. Our preclinical data supports a role for the clinical investigation of the bromodomain inhibitor CPI203 combined with bortezomib or alkylating agents in resistant multiple myeloma.