{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:58:47Z","timestamp":1791896327479,"version":"4.3.4"},"reference-count":83,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione CRT and AIRC IG 2019","award":["23146"],"award-info":[{"award-number":["23146"]}]},{"name":"Dana Farber\/Harvard Cancer Center SPORE in Lung Cancer","award":["1 P50 CA265826\u201301A1"],"award-info":[{"award-number":["1 P50 CA265826\u201301A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality, with therapeutic resistance continuing to limit long-term responses. Among emerging resistance mechanisms, dysregulation of nucleocytoplasmic transport has gained attention for its ability to inactivate tumor suppressor pathways. Exportin 1 (XPO1), the primary nuclear export protein, is frequently overexpressed in NSCLC and promotes the cytoplasmic mislocalization of proteins involved in cell cycle control, apoptosis, and DNA repair. This includes key regulators such as p53, FOXO, and RB, whose inactivation supports tumor progression and therapy resistance. Inhibition of XPO1 with selective inhibitors of nuclear export (SINE) compounds, including selinexor, has demonstrated the ability to restore nuclear localization and function of these proteins, thereby enhancing cellular sensitivity to DNA-damaging agents, kinase inhibitors, and immunotherapies. In preclinical NSCLC models, XPO1 inhibition has shown efficacy both as monotherapy and in combination strategies, with particular promise in KRAS- and EGFR-driven tumors. This review explores the role of XPO1 in NSCLC biology and therapy resistance, the rationale for targeting nuclear export, and the current landscape of XPO1-directed clinical development in lung cancer.<\/jats:p>","DOI":"10.3390\/cells14241991","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T10:11:23Z","timestamp":1765793483000},"page":"1991","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exportin 1 as a Therapeutic Target to Overcome Drug Resistance in Lung Cancer"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5162-5077","authenticated-orcid":false,"given":"Maria Vittoria","family":"Di Marco","sequence":"first","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10124 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1665-3594","authenticated-orcid":false,"given":"Alessandro","family":"Gasparetto","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10124 Turin, Italy"},{"name":"Department of Pathology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1564-8531","authenticated-orcid":false,"given":"Roberto","family":"Chiarle","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10124 Turin, Italy"},{"name":"Department of Pathology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Hemopathology, European Institute of Oncology (IEO), 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1324-1431","authenticated-orcid":false,"given":"Claudia","family":"Voena","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10124 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"ref_1","unstructured":"(2025, September 12). 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