Combined Inhibition of XPO1 and DNA Methylation Exerts Synergistic Effects in DLBCL

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma characterized by high rates of relapse and limited responsiveness to standard chemotherapy. Selinxor, a selective inhibitor of XPO1, exhibited antitumor activity in various cancers. However, clinical trial results revealed that selinexor monotherapy exhibited unsatisfactory efficacy in DLBCL. Our study indicated that XPO1 expression was increased in DLBCL and was correlated with poor outcomes of DLBCL patients. Comprehensive proteomic and transcriptomics analysis showed that selinexor has significant impacts on various biological processes in DLBCL. Furthermore, we explored combination strategies involving selinexor to enhance DLBCL treatment. We examined the combined effects of selinexor with decitabine (DAC) and lenalidomide (LEN), and found that selinexor exhibited a synergistic effect with DAC against DLBCL. Further analysis revealed that DAC exerted a synergistic antitumor effect with selinexor by reversing the DNMT1 expression and DNA methylation alterations induced by selinexor. Overall, these findings provided valuable insights into the global impact of selinexor on DLBCL. The combination therapy of selinexor and DAC emerges as a highly promising strategy for effectively treating DLBCL, holding great potential for clinical application.