Discovery, Validation and Mechanistic Study of XPO1 Inhibition in the Treatment of Triple-Negative Breast Cancer

XPO1 inhibitors show promise as targeted therapies for TNBC patients. New mechanistic insight into the causes leading to TNBC sensitivity to XPO1-inhibition-mediated cell death warrant further clinical trials to evaluate the safety and efficacy in TNBC.

A computational drug repurposing pipeline was used to predict patient tumor responses to hundreds of drugs. We identified XPO1 inhibitors as a candidate drug and validated its efficacy on an independent patient dataset and across various TNBC cell lines. RNA-sequencing after longitudinal XPO1 inhibition and further mechanistic studies were performed to explore and confirm the leading causes of TNBC cell sensitivity to XPO1 inhibition.

Selinexor significantly reduce the viability of a variety of TNBC cell lines. Mechanistically, selinexor induces TNBC cell death by inhibiting the NF-kB pathway through nuclear retention of NFKBIA. This effect was consistent across multiple TNBC cell lines. Conclusions: XPO1 inhibitors show promise as targeted therapies for TNBC patients. New mechanistic insight into the causes leading to TNBC sensitivity to XPO1-inhibition-mediated cell death warrant further clinical trials to evaluate the safety and efficacy in TNBC.