Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model.
Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model.
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DOI：
10.1158/1535-7163.mct-12-1151
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发表时间：
2013-06
影响因子：
5.7
通讯作者：
Van Ness BG
中科院分区：
文献类型：
--
作者：
Stessman HA;Baughn LB;Sarver A;Xia T;Deshpande R;Mansoor A;Walsh SA;Sunderland JJ;Dolloff NG;Linden MA;Zhan F;Janz S;Myers CL;Van Ness BG
多发性骨髓瘤是一种血液恶性肿瘤，其特征在于骨髓中的肿瘤性浆细胞增殖。尽管第一个上市的蛋白酶体抑制剂硼替佐米（Velcade）已成功用于治疗骨髓瘤患者，但耐药性仍然是一个新出现的问题。在这项研究中，我们通过基因表达谱（GEP）使用从Bcl-XL/Myc双转基因多发性骨髓瘤小鼠模型中创建的硼替佐米敏感（BzS）和硼替佐米耐药（BzR）细胞系对来识别硼替佐米敏感性和耐药性的特征。值得注意的是，这些BzR细胞系显示出对下一代蛋白酶体抑制剂MLN 2238和卡非佐米（Kyprolis）的交叉耐药性，但对其他抗骨髓瘤药物无交叉耐药性。我们使用连接图数据库进一步表征了对硼替佐米的反应，揭示了这些细胞系对组蛋白脱乙酰酶（HDAC）抑制剂的不同反应。此外，使用HDAC抑制剂帕比司他的体内实验证实，预测的应答者在BzR系中显示出对HDAC抑制剂的敏感性增加。这些发现表明，GEP可用于记录骨髓瘤细胞中的硼替佐米耐药性，并预测个体对其他药物类别的敏感性。最后，这些数据揭示了多发性骨髓瘤内复杂的异质性，并表明对一类药物的耐药性重新编程耐药克隆，以增加对一类不同药物的敏感性。这项研究代表了翻译药物基因组学分析的重要下一步，可能有助于了解多发性骨髓瘤患者的个性化药物治疗。
Multiple myeloma is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. Although the first-to-market proteasome inhibitor bortezomib (Velcade) has been successfully used to treat patients with myeloma, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive (BzS) and bortezomib-resistant (BzR) cell lines created from the Bcl-XL/Myc double-transgenic mouse model of multiple myeloma. Notably, these BzR cell lines show cross-resistance to the next-generation proteasome inhibitors, MLN2238 and carfilzomib (Kyprolis) but not to other antimyeloma drugs. We further characterized the response to bortezomib using the Connectivity Map database, revealing a differential response between these cell lines to histone deacetylase (HDAC) inhibitors. Furthermore, in vivo experiments using the HDAC inhibitor panobinostat confirmed that the predicted responder showed increased sensitivity to HDAC inhibitors in the BzR line. These findings show that GEP may be used to document bortezomib resistance in myeloma cells and predict individual sensitivity to other drug classes. Finally, these data reveal complex heterogeneity within multiple myeloma and suggest that resistance to one drug class reprograms resistant clones for increased sensitivity to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy for patients with multiple myeloma.