Identification of nuclear export inhibitor-based combination therapies in preclinical models of triple-negative breast cancer
•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 t...
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Published in | Translational oncology Vol. 14; no. 12; p. 101235 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Inc
01.12.2021
Neoplasia Press Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | •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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1936-5233 1936-5233 |
DOI: | 10.1016/j.tranon.2021.101235 |