Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, New York, New York.
Clin Cancer Res. 2017 Aug 1;23(15):4301-4311. doi: 10.1158/1078-0432.CCR-16-2632. Epub 2017 Mar 17.
Selinexor, a small molecule that inhibits nuclear export protein XPO1, has demonstrated efficacy in solid tumors and hematologic malignancies with the evidence of clinical activity in sarcoma as a single agent. Treatment options available are very few, and hence the need to identify novel targets and strategic therapies is of utmost importance. The mechanistic effects of selinexor in sarcomas as a monotherapy and in combination with proteasome inhibitor, carfilzomib, across a panel of cell lines and few in xenograft mouse models were investigated. Selinexor induced IκB nuclear localization as a single agent, and the effect was enhanced by stabilization of IκB when pretreated with the proteasome inhibitor carfilzomib. This stabilization and retention of IκB in the nucleus resulted in inhibition of NFκB and transcriptional suppression of the critical antiapoptotic protein, survivin. Treatment of carfilzomib followed by selinexor caused selinexor-sensitive and selinexor-resistant cell lines to be more sensitive to selinexor as determined by an increase in apoptosis. This was successfully demonstrated in the MPNST xenograft model with enhanced tumor suppression. The subcellular distributions of IκB and NFκB are indicative of carcinogenesis. Inhibition of XPO1 results in intranuclear retention of IκB, which inhibits NFκB and thereby provides a novel mechanism for drug therapy in sarcoma. This effect can be further enhanced in relatively selinexor-resistant sarcoma cell lines by pretreatment with the proteasome inhibitor carfilzomib. Because of these results, a human clinical trial with selinexor in combination with a proteasome inhibitor is planned for the treatment of sarcoma. .
Selinexor 是一种抑制核输出蛋白 XPO1 的小分子药物，在实体瘤和血液恶性肿瘤中表现出疗效，在肉瘤中作为单一药物具有临床活性的证据。现有的治疗选择非常有限，因此确定新的靶点和策略性治疗方法至关重要。本研究旨在研究 selinexor 作为单一药物以及与蛋白酶体抑制剂卡非佐米联合应用于一系列细胞系和少数异种移植小鼠模型中的肉瘤的作用机制。Selinexor 作为单一药物可诱导 IκB 核定位，当用蛋白酶体抑制剂卡非佐米预处理时，IκB 的稳定性增强，从而增强了这种作用。这种 IκB 在核内的稳定和保留导致 NFκB 抑制和关键抗凋亡蛋白 survivin 的转录抑制。用卡非佐米预处理后再用 selinexor 处理导致对 selinexor 更敏感的 selinexor 敏感和耐药细胞系对 selinexor 更敏感，这可通过增加细胞凋亡来确定。在 MPNST 异种移植模型中成功地证明了这一点，肿瘤抑制作用增强。IκB 和 NFκB 的亚细胞分布提示致癌作用。XPO1 的抑制导致 IκB 的核内保留，从而抑制 NFκB，从而为肉瘤的药物治疗提供了一种新的机制。用蛋白酶体抑制剂卡非佐米预处理相对耐药的肉瘤细胞系可进一步增强这种作用。由于这些结果，计划进行一项 selinexor 联合蛋白酶体抑制剂治疗肉瘤的人体临床试验。
