Mechanism and therapeutic efficacy of the XPO1 inhibitor selinexor in refractory/relapsed EBV-positive NK cell lymphoma

Abstract Introduction: Refractory/relapsed Epstein-Barr virus (EBV)-positive NK cell lymphoma demonstrates poor response to existing therapies, and is easily complicated by haemophagocytic lymphohistiocytosis (HLH) with short survival and poor prognosis. Selinexor, a selective inhibitor of exportin 1 (XPO1), exhibits antitumor effects by regulating the nuclear export of various tumour-associated proteins, as well as broad-spectrum antiviral activity. This study comprehensively investigated the therapeutic effects of selinexor on EBV-positive NK cell lymphoma and its underlying molecular mechanisms. Methods: In this study, we evaluated the function of selinexor in EBV-positive NK lymphoma cell lines (SNK-6, YT and NKYS) by cell proliferation assay using CCK8 kit, cell cycle and apoptosis analysis using flow cytometry. Mechanistic studies evaluated expression and nuclear-cytoplasmic transport of molecules on the IL10-JAK/STAT-MYC key axis. In addition, three refractory/relapsed EBV-positive NK cell lymphoma patients treated with selinexor in our center were retrospectively analyzed. The efficacy and safety of selinexor were evaluated. Results: XPO1 was highly expressed in EBV-positive NK lymphoma cell lines. XPO1 inhibitor selinexor significantly inhibited tumor cell proliferation, induced cell apoptosis, arrested cell cycle and downregulated the expression and secretion of IL-10 in vitro. Mechanistically, further experiments demonstrated that selinexor can inhibit nuclear export of MYC mRNA and STAT3 protein, as evidenced by decreased cytoplasmic levels of both molecules and increased nuclear-to-cytoplasmic ratios with statistically significant differences following selinexor administration. The use of selinexor in combination with chemotherapy showed favorable clinical outcomes in three refractory/relapsed EBV-positive NK cell lymphoma patients: all three patients experienced a decrease in EBV copy number and HLH-related indicators such as ferritin after treatment. Conclusions: Overall, this study revealed the mechanism of XPO1 inhibitor selinexor targeting the IL10-JAK/STAT-MYC pathway to inhibit EBV-positive NK cell lymphoma, validating its potential as a novel therapeutic strategy for patients with relapsed/refractory EBV-positive NK cell lymphoma.