Disruption of IRE1α through its kinase domain attenuates multiple myeloma
Disruption of IRE1α through its kinase domain attenuates multiple myeloma
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DOI：
10.1073/pnas.1906999116
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发表时间：
2019-08-13
影响因子：
11.1
通讯作者：
Ashkenazi, Avi
中科院分区：
文献类型：
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作者：
Harnoss, Jonathan M.;Le Thomas, Adrien;Ashkenazi, Avi
多发性骨髓瘤（MM）由恶性免疫球蛋白（IG）分泌浆细胞引起，尽管治疗进展，但仍然是不可治愈的，通常是致命的疾病。未折叠蛋白反应传感器IRE 1 alpha通过部署激酶-核糖核酸内切酶模块来激活转录因子XBP 1 s，从而支持蛋白分泌。MM细胞可能选择IRE 1 α-XBP 1 s通路;然而，IRE 1 α作为潜在MM治疗靶点的有效性存在争议。IRE 1 α或XBP 1的遗传破坏或药理学IRE 1 α激酶抑制可减弱小鼠MM肿瘤的皮下或正向转移生长，并增强两种已确立的一线抗骨髓瘤药物硼替佐米和来那度胺的疗效。在机制上，IRE 1 α扰动抑制内质网相关降解机制的关键组分的表达，以及IG轻链和已知促进MM生长的细胞因子和趋化因子的分泌。在美国和欧盟的队列中，选择性IRE 1 α激酶抑制降低了CD 138（+）浆细胞的活力，而保留了来自新诊断或治疗后复发MM患者骨髓的CD 138（-）细胞。有效的IRE 1 α抑制可通过胰腺微胰岛和体外原代肝细胞的活力，以及小鼠正常组织的稳态，维持葡萄糖诱导的胰岛素分泌。这些结果为开发用于MM治疗的IRE 1 α激酶导向抑制剂奠定了坚实的理论基础。
Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1 alpha supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1 alpha-XBP1s pathway; however, the validity of IRE1 alpha as a potential MM therapeutic target is controversial. Genetic disruption of IRE1 alpha or XBP1s, or pharmacologic IRE1 alpha kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1 alpha perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1 alpha kinase inhibition reduced viability of CD138(+) plasma cells while sparing CD138(-) cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US-and European Union-based cohorts. Effective IRE1 alpha inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1 alpha for MM therapy.