A highly potent small-molecule antagonist of exportin-1 selectively eliminates CD44+CD24- enriched breast cancer stem-like cells
A highly potent small-molecule antagonist of exportin-1 selectively eliminates CD44+CD24- enriched breast cancer stem-like cells
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一种高效的 Exportin-1 小分子拮抗剂，选择性消除富含 CD44 CD24 的乳腺癌干细胞样细胞
DOI：
10.1016/j.drup.2022.100903
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发表时间：
2022-12-01
影响因子：
24.3
通讯作者：
Yang, Yongliang
中科院分区：
文献类型：
--
作者：
Liu, Caigang;Zhang, Yixiao;Yang, Yongliang
乳腺癌干细胞(BCSCs)被认为是三阴性乳腺癌(TNBC)复发、转移和耐药的根本原因。在此，我们报道了一种高效的Exportin-1小分子拮抗剂LFS-1107的发现和生物学评价。通过核输出功能实验、生物分子层干涉结合实验和C528S突变细胞系实验，确定Exportin-1(又称CRM1)是LFS-1107的主要细胞靶点。我们发现LFS-1107在低纳摩尔浓度下对TNBC肿瘤细胞有明显的抑制作用，并且LFS-1107可以选择性地清除CD44(+)、CD24(-)的BCSCs。我们证明了LFS-1107可以诱导Survivin的核滞留，从而强烈抑制STAT3的反式激活能力和下游茎调控因子的表达。LFS-1107能显著抑制小鼠移植瘤生长，清除残留肿瘤组织中的BCSCs。此外，与几种已批准的抗癌药物相比，LFS-1107可以显著消融患者来源的TNBC肿瘤有机物(PDTO)。最后，我们发现LFS-1107可以增强化疗药物的杀伤作用，下调多药耐药相关蛋白靶点。这些新的发现提供了将LFS-1107定义为一种有前途的治疗药物的临床前证据，以耗尽BCSCs用于治疗TNBC。
Breast cancer stem-like cells (BCSCs) have been suggested as the underlying cause of tumor recurrence, metastasis and drug resistance in triple-negative breast cancer (TNBC). Here, we report the discovery and biological evaluation of a highly potent small-molecule antagonist of exportin-1, LFS-1107. We ascertained that exportin-1 (also named as CRM1) is a main cellular target of LFS-1107 by nuclear export functional assay, biolayer interferometry binding assay and C528S mutant cell line. We found that LFS-1107 significantly inhibited TNBC tumor cells at low-range nanomolar concentration and LFS-1107 can selectively eliminate CD44(+)CD24(-) enriched BCSCs. We demonstrated that LFS-1107 can induce the nuclear retention of Survivin and consequent strong suppression of STAT3 transactivation abilities and the expression of downstream stemness regulators. Administration of LFS-1107 can strongly inhibit tumor growth in mouse xenograft model and eradicate BCSCs in residual tumor tissues. Moreover, LFS-1107 can significantly ablate the patient-derived tumor organoids (PDTOs) of TNBC as compared to a few approved cancer drugs. Lastly, we revealed that LFS-1107 can enhance the killing effects of chemotherapy drugs and downregulate multidrug resistance related protein targets. These new findings provide preclinical evidence of defining LFS-1107 as a promising therapeutic agent to deplete BCSCs for the treatment of TNBC.