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

• Published in: Translational oncology Vol. 14; no. 12; p. 101235
• Main Authors: Rashid, Narmeen S., Hairr, Nicole S., Murray, Graeme, Olex, Amy L., Leftwich, Tess J., Grible, Jacqueline M., Reed, Jason, Dozmorov, Mikhail G., Harrell, J. Chuck
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.12.2021; Neoplasia Press; Elsevier
• Subjects: Breast cancer; GSK2126458; KPT-330; Original Research; TNBC; XPO1; GSK2126458; KPT-330; Breast cancer; XPO1; TNBC
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2021.101235

•High-throughput drug screening reveals promising therapeutic candidates for TNBC.•KPT-330, an XPO1 inhibitor, and GSK2126458 exhibit synergism in preclinical models of TNBC.•XPO1 is overexpressed in basal-like breast tumors.•XPO1 expression is associated with PIK3CA, MTOR, and MKI67 expression at the single-cell level.•XPO1 overexpression in basal-like patients is associated with greater rates of metastases. 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.