Abstract 838: The novel eIF4A inhibitor synergizes potently with the XPO-1 inhibitor in T-cell lymphoma

Abstract Malignant lymphomas are categorized into B-cell and T-cell lymphomas. While treatment outcomes for B-cell lymphoma have significantly improved with targeted therapies and cellular treatments, T-cell lymphoma remains a therapeutic challenge due to the lack of standardized first-line treatments. Consequently, T-cell lymphoma exhibits lower remission rates, higher relapse rates, and poor overall prognosis. Although T-cell lymphomas account for only 15-20% of all malignant lymphomas, their incidence is notably higher in Asia compared to Western countries, making Korea an ideal location for research on this disease. Also, T-cell lymphoma (TCL) is an aggressive malignancy with poor prognosis, characterized by high relapse rates and limited therapeutic options. Novel therapeutic approaches are urgently needed to improve outcomes for patients with TCL. Previous studies have demonstrated the efficacy of eIF4A inhibitors in downregulating oncogenic protein synthesis and inducing cell death in various lymphoma models. We hypothesized that the combination of eIF4A inhibitor (CR-1-31-B) and XPO-1 inhibitor (Selinexor) would exhibit synergistic anti-lymphoma activity in TCL and have potential clinical applications. The anti-lymphoma effects of CR-1-31-B in combination with a XPO-1 inhibitor were evaluated in TCL cell lines using flow cytometry. Cell apoptosis assays were performed at increasing concentrations of CR-1-31-B and the XPO-1 inhibitor alone, as well as in combination, over 48 hours. To investigate the molecular mechanisms underlying the observed synergistic effects in TCL, RNA-seq profiling was conducted on cells treated with single agents and the combination therapy. Gene set enrichment analysis (GSEA) was performed to identify pathways involved in the combination's mechanism of action. CR-1-31-B and the XPO-1 inhibitor demonstrated concentration- and time-dependent cytotoxicity in TCL cell lines at low nanomolar concentrations. The combination of the eIF4A inhibitor and the XPO-1 inhibitor showed strong synergistic effects in all tested TCL cell lines (p<0.0001). RNA-seq profiling revealed that the transcriptional signature of the combination therapy was distinct from that of single-agent treatments. The combination of eIF4A inhibitor and XPO-1 inhibitor demonstrates potent anti-lymphoma activity in T-cell lymphoma. This novel combination represents a promising therapeutic strategy for patients with TCL, warranting further preclinical investigations and potential clinical translation. Citation Format: So-Young Seol, Chung Hyun Park, Soo Jeong Kim, Hyunsoo Cho, Jin Seok Kim, Yu Ri Kim. The novel eIF4A inhibitor synergizes potently with the XPO-1 inhibitor in T-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 838.