Identification of nuclear export inhibitor-based combination therapies in preclinical models of triple-negative breast cancer

• Main Authors: Narmeen S. Rashid, Nicole S. Hairr, Graeme Murray, Amy L. Olex, Tess J. Leftwich, Jacqueline M. Grible, Jason Reed, Mikhail G. Dozmorov, J. Chuck Harrell
• Format: Article
• Language: English
• Published: Elsevier 2021-12-01
• Series: Translational Oncology
• Subjects: Breast cancer; TNBC; KPT-330; GSK2126458; XPO1
• Online Access: http://www.sciencedirect.com/science/article/pii/S1936523321002278

An estimated 284,000 Americans will be diagnosed with breast cancer in 2021. Of these individuals, 15–20% have basal-like triple-negative breast cancer (TNBC), which is known to be highly metastatic. Chemotherapy is standard of care for TNBC patients, but chemoresistance is a common clinical problem. There is currently a lack of alternative, targeted treatment strategies for TNBC; this study sought to identify novel therapeutic combinations to treat basal-like TNBCs. For these studies, four human basal-like TNBC cell lines were utilized to determine the cytotoxicity profile of 1363 clinically-used drugs. Ten promising therapeutic candidates were identified, and synergism studies were performed in vitro. Two drug combinations that included KPT-330, an XPO1 inhibitor, were synergistic in all four cell lines. In vivo testing of four basal-like patient-derived xenografts (PDX) identified one combination, KPT-330 and GSK2126458 (a PI3K/mTOR inhibitor), that decreased tumor burden in mice significantly more than monotherapy with either single agent. Bulk and single-cell RNA-sequencing, immunohistochemistry, and analysis of published genomic datasets found that XPO1 was abundantly expressed in human basal-like TNBC cell lines, PDXs, and patient tumor samples. Within basal-like PDXs, XPO1 overexpression was associated with increased proliferation at the cellular level. Within patient datasets, XPO1 overexpression was correlated with greater rates of metastasis in patients with basal-like tumors. These studies identify a promising potential new combination therapy for patients with basal-like breast cancer.