Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
Karyopharm Therapeutics Inc, Newton, MA.
Blood Adv. 2023 Jun 27;7(12):2926-2937. doi: 10.1182/bloodadvances.2021006638.
Selinexor (KPT-330) is a small molecule inhibitor of XPO1, which mediates the transport of tumor suppressor proteins, oncogene messenger RNAs, and other proteins involved in governing cell growthfrom the cell nucleus to the cytoplasm. It is overexpressed in many cancer types. Because eukaryotic translation initiator factor 4E (eIF4E) plays a critical role in protein translation in cancer cells in multiple myeloma (MM), we evaluated the effectiveness of combined inhibition of protein translation and nuclear export in MM. Selinexor, an inhibitor of nuclear protein export, dose-dependently decreased eIF4E, IKZF1, and c-MYC protein levels. Using a doxycycline-inducible-pLKO-Tet-On vector, knockdown of eIF4E significantly enhanced the antiproliferative effects of selinexor, sensitized resistant MM cells to selinexor, and increased apoptosis in MM cells. Immunofluorescent analysis of MM cells showed that the combined treatment increased the localization of residual eIF4E to the nucleus compared with selinexor-only treatment. The overexpression of eIF4E at least partially rescued the effects of selinexor in MM cells by reducing G1 cell cycle arrest and increasing the selinexor-IC50 10-fold. Moreover, the combination of selinexor with pharmacologic inhibitors of protein translation showed synergistic anti-MM effects. These results suggest a synergistic anti-MM effect of selinexor combined with eIF4E inhibitors in vitro. Our work provides a better understanding of the potential mechanism of resistance to selinexor and a rationale for combining selinexor with eIF4E inhibitors for the treatment of MM.
Selinexor（KPT-330）是一种 XPO1 的小分子抑制剂，可介导肿瘤抑制蛋白、致癌基因信使 RNA 和其他参与控制细胞生长的蛋白从细胞核转运到细胞质。它在许多癌症类型中过表达。由于真核翻译起始因子 4E（eIF4E）在多发性骨髓瘤（MM）的癌细胞中对蛋白质翻译起关键作用，我们评估了联合抑制蛋白质翻译和核输出在 MM 中的有效性。Selinexor 是一种核蛋白输出抑制剂，可剂量依赖性地降低 eIF4E、IKZF1 和 c-MYC 蛋白水平。使用四环素诱导的 pLKO-Tet-On 载体，eIF4E 的敲低显著增强了 selinexor 的抗增殖作用，使耐药 MM 细胞对 selinexor 敏感，并增加了 MM 细胞的凋亡。MM 细胞的免疫荧光分析表明，与仅用 selinexor 处理相比，联合治疗增加了残留 eIF4E 向细胞核的定位。eIF4E 的过表达至少部分通过减少 G1 细胞周期阻滞和将 selinexor-IC50 增加 10 倍来挽救 MM 细胞中 selinexor 的作用。此外，selinexor 与蛋白翻译的药理学抑制剂联合使用显示出协同的抗 MM 作用。这些结果表明，selinexor 与 eIF4E 抑制剂联合在体外具有协同抗 MM 作用。我们的工作提供了对 selinexor 耐药潜在机制的更好理解，并为 selinexor 与 eIF4E 抑制剂联合治疗 MM 提供了依据。
