Targeting CDK4/6 impairs RB1/E2F activity to overcome the resistance to selinexor in Nature killer/T-cell lymphoma

XPO1 is frequently overexpressed in multiple hematological malignancies, highlighting the attractiveness of targeting XPO1 as a therapeutic strategy. However, the therapeutic potential of XPO1 inhibition in NKTL was still not well documented. Here, we demonstrated that XPO1 is highly expressed in NKTL and is correlated with poor prognosis, suggesting that XPO1 is a potential target in NKTL. In addition, we identified YY1 as a transcriptional factor that bound to XPO1 promoter to activate its expression. Functional studies revealed that pharmacological inhibition of XPO1 using selinexor effectively blocks CDK4/6-pRB-E2F-c-Myc signaling, resulting in cell cycle arrest and apoptosis in sensitive cells. Transcriptomic analysis identified that dysfunction in cell cycle machinery may contribute to selinexor resistance, as resistant cells restore the expression of cycle-related genes to evade cell death. High-throughput screening utilizing a panel of 130 cell cycle inhibitors identified CDK4/6 inhibitors as sensitizers to selinexor in resistant cells. Mechanistically, the combination of CDK4/6 inhibitors and selinexor led to an enhanced inhibition of pRB-E2F-c-Myc signaling. Additionally, compassionate use of selinexor in combination with chemotherapy (gemcitabine, oxaliplatin) in three Refectory/Relapsed (R/R) NKTL patients achieved favorable clinical outcomes. Our data unveil a novel mechanism by which XPO1 inhibition blocks CDK4/6-pRb-E2F-c-Myc signaling, providing a rationale for the combination of CDK4/6 with XPO1 inhibitors for NKTL treatment.