{"doi":"10.3390/cancers16233980","title":"Discovery, Validation and Mechanistic Study of XPO1 Inhibition in the Treatment of Triple-Negative Breast Cancer","abstract":"Background/Objectives: 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 has not been fully characterized. This study investigates the potential of repurposing selinexor, an FDA-approved XPO1 inhibitor, as a novel therapeutic options for TNBC. Methods: A computational drug repurposing pipeline was used to predict patient tumor responses to hundreds of drugs. We identified XPO1 inhibitors as a candidate drug and validated its efficacy on an independent patient dataset and across various TNBC cell lines. RNA-sequencing after longitudinal XPO1 inhibition and further mechanistic studies were performed to explore and confirm the leading causes of TNBC cell sensitivity to XPO1 inhibition. Results: Selinexor significantly reduce the viability of a variety of TNBC cell lines. Mechanistically, selinexor induces TNBC cell death by inhibiting the NF-kB pathway through nuclear retention of NFKBIA. This effect was consistent across multiple TNBC cell lines. Conclusions: XPO1 inhibitors show promise as targeted therapies for TNBC patients. New mechanistic insight into the causes leading to TNBC sensitivity to XPO1-inhibition-mediated cell death warrant further clinical trials to evaluate the safety and efficacy in TNBC.","journal":"Cancers","year":2024,"id":482399,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":754937,"name":"Robert F. Gruener","orcid":"0000-0002-8166-2772","position":1,"is_corresponding":false},{"id":225288,"name":"Adam M Lee","orcid":"0000-0003-2141-4264","position":2,"is_corresponding":false},{"id":12358,"name":"R. Stephanie Huang","orcid":"0000-0002-9862-0368","position":3,"is_corresponding":false},{"id":949436,"name":"Amy Paulson","orcid":"0000-0001-9188-3969","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:07:14.349221Z","pmid":"39682167","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":[]}