Discovery, Validation and Mechanistic study of XPO1 inhibition in the Treatment of Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with limited treatment options. This study investigates the potential of repurposing selinexor, an XPO1 inhibitor, as a novel therapeutic option for TNBC. By utilizing a computational drug repurposing approach, XPO1 inhibitors were identified to be preferentially sensitive in TNBC compared to other breast cancer subtypes and its efficacy validated in an independent patient dataset and across various TNBC cell lines. Using RNA-sequencing after longitudinal XPO1 inhibition in a panel of TNBC cell lines and western blotting, we reveal that XPO1 inhibitor induces TNBC cell death by inhibiting the NF-kB pathway through nuclear retention of NFKBIA, a key regulator of this pathway. These findings suggest that XPO1 inhibitors could be an effective targeted therapy for TNBC and paves the way for more personalized treatment strategies offering hope for better outcomes in TNBC patients.