Dual targeting of protein translation and nuclear protein export results in enhanced anti-myeloma effects.

Selinexor (KPT-330) is a small molecule inhibitor of XPO1 (exportin 1, Chromosome Region Maintenance 1/CRM1), which mediates the transport of tumor suppressor proteins, oncogene mRNAs and other proteins involved in governing cell growth, from the cell nucleus to the cytoplasm. It is often overexpressed in many cancer types. Since eukaryotic translation initiator factor 4E (eIF4E) plays a critical role in cancer protein translation in multiple myeloma (MM), we evaluated the effectiveness of combined inhibition of protein translation and with a nuclear export inhibitor in MM. Selinexor, an nuclear protein inhibitor of nuclear protein export, dose-dependently decreased eIF4E, IKZF1 and c-MYC protein levelsinhibits eIF4E-directed translation of oncoproteins such as IKZF1 and c-MYC.. 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 localization of residual eIF4E to the nucleus compared with selinexor treatment alone. In vivo studies showed that eIF4E knockdown enhanced the anti-tumor activity of selinexor in mice. Overexpression of eIF4E at least partially rescued the effects of selinexor in MM cells by reducing G1 cell cycle arrest as well as 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 effects 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.