{"doi":"10.1016/j.tranon.2021.101235","title":"Identification of nuclear export inhibitor-based combination therapies in preclinical models of triple-negative breast cancer","abstract":"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.","journal":"Translational Oncology","year":2021,"id":181570,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9432,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":732553,"name":"Nicole S. Hairr","orcid":"0000-0002-9128-1690","position":1,"is_corresponding":false},{"id":732554,"name":"Graeme Murray","orcid":"0000-0002-6503-9294","position":2,"is_corresponding":false},{"id":571568,"name":"Amy L. Olex","orcid":"0000-0001-8064-521X","position":3,"is_corresponding":false},{"id":732555,"name":"Tess J. Leftwich","orcid":"0000-0002-5586-5023","position":4,"is_corresponding":false},{"id":704350,"name":"Jacqueline M. Grible","orcid":null,"position":5,"is_corresponding":false},{"id":571569,"name":"Jason Reed","orcid":"0000-0002-3314-8699","position":6,"is_corresponding":false},{"id":265858,"name":"Mikhail G. Dozmorov","orcid":"0000-0002-0086-8358","position":7,"is_corresponding":false},{"id":292566,"name":"J. Chuck Harrell","orcid":"0000-0003-3541-8418","position":8,"is_corresponding":false},{"id":732552,"name":"Narmeen S Rashid","orcid":"0000-0003-2321-2711","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-18T23:48:05.146883Z","pmid":"34628286","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}