Modulating proteasome inhibitor tolerance in multiple myeloma: an alternative strategy to reverse inevitable resistance.
Modulating proteasome inhibitor tolerance in multiple myeloma: an alternative strategy to reverse inevitable resistance.
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调节多发性骨髓瘤对蛋白酶体抑制剂的耐受性：逆转不可避免耐药性的替代策略。
DOI：
10.1038/s41416-020-01191-y
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发表时间：
2021-03
影响因子：
8.8
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Ge M;Qiao Z;Kong Y;Liang H;Sun Y;Lu H;Xu Z;Liu H
多发性骨髓瘤(MM)对蛋白酶体抑制剂(PI)的耐药性是其治疗成功的主要障碍。已经提出了许多PI抗性的机制；然而，我们对于PI抗性是如何不可避免地获得和逆转的机制的理解仍然不完整。将复发后的MM患者、MM细胞系和小鼠模型用来产生匹配的耐药细胞和逆转细胞。RNA测序和生物信息学分析被用来评估异常的表观遗传调节因子。用体外和体内方法鉴定耐PI细胞和治疗效果。经PI处理后，MM细胞进入慢周期和可逆耐药状态。这种可逆的表型与表观遗传可塑性有关，在复发的MM患者中涉及耐受性而不是持久性。与持续的PI单独治疗相比，组蛋白脱乙酰酶抑制剂和高剂量间歇治疗联合治疗MM可以通过防止PI耐受细胞的出现而更有效地治疗MM。治疗的基础是逆转多发性骨髓瘤患者异常的表观遗传调节因子。我们提出了一种替代的非突变PI耐药机制，解释了为什么PI复发是不可避免的，以及为什么患者在“药物假期”后重新变得敏感。我们的研究还提出了表观遗传学消除耐药细胞的策略。
Resistance to proteasome inhibitors (PIs) is a major obstacle to the successful treatment of multiple myeloma (MM). Many mechanisms have been proposed for PI resistance; however, our mechanistic understanding of how PI resistance is inevitably acquired and reversed remains incomplete. MM patients after bortezomib relapse, MM cell lines and mouse models were used to generate matched resistant and reversed cells. RNA sequencing and bioinformatics analyses were employed to assess dysregulated epigenetic regulators. In vitro and in vivo procedures were used to characterise PI-tolerant cells and therapeutic efficacy. Upon PI treatment, MM cells enter a slow-cycling and reversible drug-tolerant state. This reversible phenotype is associated with epigenetic plasticity, which involves tolerance rather than persistence in patients with relapsed MM. Combination treatment with histone deacetylase inhibitors and high-dosage intermittent therapy, as opposed to sustained PI monotherapy, can be more effective in treating MM by preventing the emergence of PI-tolerant cells. The therapeutic basis is the reversal of dysregulated epigenetic regulators in MM patients. We propose an alternative non-mutational PI resistance mechanism that explains why PI relapse is inevitable and why patients regain sensitivity after a ‘drug holiday’. Our study also suggests strategies for epigenetic elimination of drug-tolerant cells.
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