Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?
Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?
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近年来，治疗方面的进步，特别是新药的使用，极大地提高了多发性骨髓瘤（MM）患者的生存率。然而，频繁的复发和耐药性仍然是未解决的问题。内质网应激（Endoplasmic reticulum stress， ERS）在MM中较正常浆细胞升高，被认为是MM的致命弱点。本文综述了目前关于ERS反应如何影响MM发病机制和耐药的知识，并为开发新的治疗策略以改善MM患者的临床结果提供了启示。多发性骨髓瘤（MM）是第二常见的血液恶性肿瘤，由骨髓内恶性浆细胞克隆性增殖引起。尽管在过去的二十年中，新型药物取得了重大进展，但MM患者经常出现治疗耐药，特别是对硼替佐米（一种被批准用于MM治疗的一流蛋白酶体抑制剂）的耐药。作为高分泌的单克隆蛋白产生细胞，MM细胞的特征是上载内质网应激（ERS），并且严重依赖ERS应答来生存。已经做出了巨大的努力来说明MM细胞如何通过调节ERS反应来适应治疗性应激。在这篇综述中，我们总结了目前关于ERS反应途径影响MM细胞命运和对治疗反应的机制的知识。此外，基于临床前研究取得的可喜结果，我们讨论了应用ERS调节剂克服MM耐药的前景。
Advances in treatment, especially with novel drugs, have dramatically improved the survival of multiple myeloma (MM) patients recently. However, frequent relapses and drug resistance remain unsolved issues. Endoplasmic reticulum stress (ERS) is elevated in MM compared to normal plasma cells, and is regarded as the Achilles’ heel of MM. This review summarizes the current knowledge of how ERS response influences the pathogenesis and drug-resistance of MM, and provides inspiration for novel therapeutic strategies to improve clinical outcomes of MM patients by targeting ERS. Multiple myeloma (MM) is the second most common hematologic malignancy, resulting from the clonal proliferation of malignant plasma cells within the bone marrow. Despite significant advances that have been made with novel drugs over the past two decades, MM patients often develop therapy resistance, especially to bortezomib, the first-in-class proteasome inhibitor that was approved for treatment of MM. As highly secretory monoclonal protein-producing cells, MM cells are characterized by uploaded endoplasmic reticulum stress (ERS), and rely heavily on the ERS response for survival. Great efforts have been made to illustrate how MM cells adapt to therapeutic stresses through modulating the ERS response. In this review, we summarize current knowledge on the mechanisms by which ERS response pathways influence MM cell fate and response to treatment. Moreover, based on promising results obtained in preclinical studies, we discuss the prospect of applying ERS modulators to overcome drug resistance in MM.
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影响因子：
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