Dual epigenetic and nuclear export inhibition by chidamide and selinexor in high grade B-cell lymphomas via survivin and PI3K/AKT inhibition

BACKGOUND: High-grade B-cell lymphoma with concurrent MYC and BCL2/BCL6 rearrangements (HGBL-DHL) is a highly aggressive disease that is resistant to conventional first-line immunochemotherapeutic regimens. This resistance necessitates the exploration of innovative therapeutic strategies. RESULT: In this study, the combination of chidamide and selinexor showed significant synergistic antilymphoma effects in the treatment of HGBL-DHL. The synergistic effects were evidenced by the inhibition of cell proliferation, induction of apoptosis, and perturbation of the cell cycle in cell lines, as assessed by Cell Counting Kit-8, Annexin V/PI staining, and PI staining assays. Furthermore, in a xenograft mouse model of HGBL-DHL, this combination therapy markedly reduced the tumor burden without causing lethal toxicity. At the mechanistic level, the combination of chidamide and selinexor resulted in the synergistic downregulation of survivin and the PI3K/AKT signaling pathway. This dual inhibition was attributed to the interactive effects of the two drugs. The downregulation of key downstream targets of the PI3K/AKT pathway, including c-Myc, MCL1, BCL-XL, cyclin A2, and survivin, was synergistic and aligned with the phenotypic outcomes. Notably, survivin, an anti-apoptotic gene, underwent transcriptional repression by FOXO1 at the level of epigenetic regulation. Chidamide combined with selinexor synergistically down-regulated survivin in both the nucleus, cytoplasm and total protein levels via HDAC/FOXO1/survivin, HDAC3/PI3K/AKT/XPO1/survivin, XPO1/FOXO1/survivin, and XPO1/survivin axes. CONCLUSION: Our preclinical data highlighted the potential synergistic efficacy of chidamide and selinexor in targeting HGBL-DHL, providing a rationale for further clinical investigation of this therapeutic combination for the treatment of this refractory disease.