Increased resistance to proteasome inhibitors in multiple myeloma mediated by cIAP2--implications for a combinatorial treatment.
Increased resistance to proteasome inhibitors in multiple myeloma mediated by cIAP2--implications for a combinatorial treatment.
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DOI：
10.18632/oncotarget.4139
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发表时间：
2015-08-21
期刊：
影响因子：
--
通讯作者：
Jernberg Wiklund H
中科院分区：
文献类型：
--
作者：
Fristedt Duvefelt C;Lub S;Agarwal P;Arngården L;Hammarberg A;Maes K;Van Valckenborgh E;Vanderkerken K;Jernberg Wiklund H
尽管为多发性骨髓瘤（MM）引入了新的治疗选择，但大多数患者由于耐药的发展而复发。揭示耐药性的新机制可能会导致识别可能的组合治疗靶点。使用TRAF 3缺失/突变的MM细胞系，我们评估了细胞凋亡抑制因子2（cIAP 2）在耐药性中的作用，并揭示了这种耐药性的可能机制以及通过组合治疗克服这种耐药性的可能策略。在MM中，cIAP 2是异常NF-κB信号传导的基因特征的一部分，在MM患者中不均匀表达。在cIAP 2过表达细胞中，观察到对蛋白酶体抑制剂硼替佐米、MG 132和卡非佐米的敏感性降低。基因表达分析显示，440个基因的差异表达，由于cIAP 2过表达。重要的是，数据暗示cIAP是TRAF 3缺失/突变的MM群体中组合治疗的合理靶标。事实上，我们发现用IAP抑制剂AT-406处理增强了硼替佐米在所研究的细胞系中的抗MM作用。总之，我们的结果表明，cIAP 2是介导TRAF 3缺失/突变的MM细胞中硼替佐米耐药性的重要因素，因此应被视为联合治疗的靶点。
Despite the introduction of new treatment options for multiple myeloma (MM), a majority of patients relapse due to the development of resistance. Unraveling new mechanisms underlying resistance could lead to identification of possible targets for combinatorial treatment. Using TRAF3 deleted/mutated MM cell lines, we evaluated the role of the cellular inhibitor of apoptosis 2 (cIAP2) in drug resistance and uncovered the plausible mechanisms underlying this resistance and possible strategies to overcome this by combinatorial treatment. In MM, cIAP2 is part of the gene signature of aberrant NF-κB signaling and is heterogeneously expressed amongst MM patients. In cIAP2 overexpressing cells a decreased sensitivity to the proteasome inhibitors bortezomib, MG132 and carfilzomib was observed. Gene expression analysis revealed that 440 genes were differentially expressed due to cIAP2 overexpression. Importantly, the data imply that cIAPs are rational targets for combinatorial treatment in the population of MM with deleted/mutated TRAF3. Indeed, we found that treatment with the IAP inhibitor AT-406 enhanced the anti-MM effect of bortezomib in the investigated cell lines. Taken together, our results show that cIAP2 is an important factor mediating bortezomib resistance in MM cells harboring TRAF3 deletion/mutation and therefore should be considered as a target for combinatorial treatment.