Abstract 5032: Discovery of XPO1 as a therapeutic target in TNBC: Mechanistic insights and preclinical validation

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with limited treatment options. The nuclear export protein XPO1 has emerged as a potential therapeutic target in cancer, but its role in TNBC hasn’t been fully characterized. OBJECTIVES: This study screens, nominates, and investigates the potential of repurposing selinexor, an FDA-approved XPO1 inhibitor, as a novel therapeutic option for TNBC. METHODS: We utilized a computational drug repurposing pipeline to predict breast cancer patient tumor responses to hundreds of drugs. We then stratified patient tumor’s predicted sensitivities by breast cancer subtype and focused on drugs preferentially sensitive towards TNBC. We identified XPO1 inhibitors as the top candidate drug and its efficacy validated in an independent patient dataset and across various TNBC cell line. Additionally, we conducted RNA-sequencing after longitudinal XPO1 inhibition in a panel of TNBC cell lines to explore the mechanism contributing to the preferential sensitivity of TNBC cells to XPO1-inhibition mediated cell death. Further mechanistic studies were conducted to validate our RNA-sequencing findings. RESULTS: Selinexor was found to significantly reduce the viability of a variety of TNBC cell lines. Mechanistically, we reveal that selinexor induces TNBC cell death by inhibiting the NF-kB pathway through nuclear retention of NFKBIA, a key regulator of this pathway. This effect was consistent across multiple TNBC cell lines of differing TNBC subtypes, confirming the broad applicability of XPO1 inhibition in TNBC treatment. CONCLUSION: This study identifies XPO1 inhibitors as a promising therapeutic candidate for TNBC patients by inhibiting the XPO1-mediated export of NFKBIA and blocking the NF-kB pathway. These findings pave the way for more personalized treatment strategies and provide a potential alternative to conventional chemotherapy. IMPLICATIONS FOR PRACTICE: Repurposing selinexor for the treatment of TNBC could accelerate the availability of targeted therapies for patients with this aggressive cancer. New mechanistic insight into the causes leading to TNBC cell specific sensitivity to XPO1-inhibition mediated cell death warrant further clinical trials to evaluate the safety and efficacy of selinexor in TNBC patients. Citation Format: Amy L. Paulson, Robert F. Gruener, Adam M. Lee, R. Stephanie Huang. Discovery of XPO1 as a therapeutic target in TNBC: Mechanistic insights and preclinical validation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5032.