Dana-Farber Cancer Institute, 44 Binney Street, Dana 1B02, Boston, MA, 02115, USA.
Cancer Metastasis Rev. 2017 Dec;36(4):561-584. doi: 10.1007/s10555-017-9707-8.
Proteasome inhibitors are one of the most important classes of agents to have emerged for the treatment of multiple myeloma in the past two decades, and now form one of the backbones of treatment. Three agents in this class have been approved by the United States Food and Drug Administration-the first-in-class compound bortezomib, the second-generation agent carfilzomib, and the first oral proteasome inhibitor, ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the 26S proteasome, which plays a critical role in the pathogenesis and proliferation of the disease. Proteasome inhibition results in multiple downstream effects, including the inhibition of NF-κB signaling, the accumulation of misfolded and unfolded proteins, resulting in endoplasmic reticulum stress and leading to the unfolded protein response, the downregulation of growth factor receptors, suppression of adhesion molecule expression, and inhibition of angiogenesis; resistance to proteasome inhibition may arise through cellular responses mediating these downstream effects. These multiple biologic consequences of proteasome inhibition result in synergistic or additive activity with other chemotherapeutic and targeted agents for myeloma, and proteasome inhibitor-based combination regimens have become established as a cornerstone of therapy throughout the myeloma treatment algorithm, incorporating agents from the other key classes of antimyeloma agents, including the immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. This review gives an overview of the critical role of the proteasome in myeloma and the characteristics of the different proteasome inhibitors and provides a comprehensive summary of key clinical efficacy and safety data with the currently approved proteasome inhibitors.
蛋白酶体抑制剂是过去二十年中治疗多发性骨髓瘤最重要的一类药物之一，现已成为治疗的重要支柱之一。该类药物中有三种已获得美国食品和药物管理局批准——首个获批的化合物硼替佐米、第二代药物卡非佐米和首个口服蛋白酶体抑制剂伊沙佐米。该类药物的成功源于骨髓瘤细胞对 26S 蛋白酶体抑制的高度敏感，这在疾病的发病机制和增殖中起着关键作用。蛋白酶体抑制会导致多种下游效应，包括 NF-κB 信号抑制、错误折叠和未折叠蛋白的积累，导致内质网应激并引发未折叠蛋白反应、生长因子受体下调、黏附分子表达抑制和血管生成抑制；对蛋白酶体抑制的耐药性可能是通过介导这些下游效应的细胞反应产生的。蛋白酶体抑制的这些多种生物学后果与骨髓瘤的其他化疗和靶向药物产生协同或相加作用，基于蛋白酶体抑制剂的联合治疗方案已成为整个骨髓瘤治疗算法的基石，纳入了其他关键类别的抗骨髓瘤药物，包括免疫调节剂、单克隆抗体和组蛋白去乙酰化酶抑制剂。这篇综述概述了蛋白酶体在骨髓瘤中的关键作用以及不同蛋白酶体抑制剂的特点，并全面总结了目前已批准的蛋白酶体抑制剂的关键临床疗效和安全性数据。
