The molecular mechanism and challenge of targeting XPO1 in treatment of relapsed and refractory myeloma.
The molecular mechanism and challenge of targeting XPO1 in treatment of relapsed and refractory myeloma.
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DOI：
10.1016/j.tranon.2022.101448
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发表时间：
2022-08
影响因子：
5
通讯作者：
Zhang, Jiwang
中科院分区：
文献类型：
--
作者：
Sellin, Mark;Berg, Stephanie;Hagen, Patrick;Zhang, Jiwang
在过去的二十年里，多发性骨髓瘤的治疗取得了重大进展。获得性耐药继续推动原发难治性MM的早期复发。XPO1过度表达和Cargo错误定位与耐药有关。XPO1抑制剂Selinexor恢复对RR-MM细胞亚群的药物敏感性。自从引入免疫调节剂、蛋白酶体抑制剂和抗CD38单抗以来，多发性骨髓瘤(MM)的治疗方案有了很大的改善；然而，由于不可避免的复发和获得性耐药，MM被认为是一种无法治愈的疾病。了解获得性耐药的分子机制将有助于创造预防复发的新策略，并有助于开发治疗复发/难治性MM患者的新疗法。目前，只有染色体17p区“双缺失”导致的TP53基因纯合性缺失/突变与预后不良有关。XPO1在RR-MM细胞中的过度表达和错误定位的令人兴奋的发现导致了一种新的治疗选择。临床研究表明，XPO1抑制剂Selinexor可以恢复RR-MM对PI和地塞米松的敏感性。我们将详细阐述多发性骨髓瘤治疗策略存在的问题，并讨论在RR-MM治疗中使用XPO1抑制剂的机制和挑战，同时讨论潜在的解决方案。
Significant progress has been made on the treatment of MM during past two decades. Acquired drug-resistance continues to drive early relapse in primary refractory MM. XPO1 over-expression and cargo mislocalization are associated with drug-resistance. XPO1 inhibitor selinexor restores drug sensitivity to subsets of RR-MM cells. Multiple myeloma (MM) treatment regimens have vastly improved since the introduction of immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies; however, MM is considered an incurable disease due to inevitable relapse and acquired drug resistance. Understanding the molecular mechanism by which drug resistance is acquired will help create novel strategies to prevent relapse and help develop novel therapeutics to treat relapsed/refractory (RR)-MM patients. Currently, only homozygous deletion/mutation of TP53 gene due to “double-hits” on Chromosome 17p region is consistently associated with a poor prognosis. The exciting discovery of XPO1 overexpression and mislocalization of its cargos in the RR-MM cells has led to a novel treatment options. Clinical studies have demonstrated that the XPO1 inhibitor selinexor can restore sensitivity of RR-MM to PIs and dexamethasone. We will elaborate on the problems of MM treatment strategies and discuss the mechanism and challenges of using XPO1 inhibitors in RR-MM therapies while deliberating potential solutions.
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影响因子：
20.3
作者：
Chen, Christine;Siegel, David;Reece, Donna
通讯作者：
Reece, Donna
影响因子：
11.4
作者：
Besse A;Stolze SC;Rasche L;Weinhold N;Morgan GJ;Kraus M;Bader J;Overkleeft HS;Besse L;Driessen C
通讯作者：
Driessen C
DOI：
10.1073/pnas.1007462107
发表时间：
2010-07-13
影响因子：
11.1
作者：
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3.3
作者：
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影响因子：
24.7
作者：
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通讯作者：
Sonneveld, Pieter