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However, resistance to these treatments remains a major clinical challenge. Raf kinase inhibitory protein (RKIP), encoded by the\n                    <jats:italic>PEBP1<\/jats:italic>\n                    gene, a metastasis suppressor, modulates key oncogenic pathways and may influence tumor aggressiveness and therapy response. Yet, its specific role in NSCLC remains unclear. This study investigates the influence of RKIP expression on NSCLC aggressiveness and explores its impact on therapy response, particularly to EGFR\u2010targeted therapies.\n                    <jats:italic>In silico<\/jats:italic>\n                    analyses revealed that lower\n                    <jats:italic>RKIP<\/jats:italic>\n                    mRNA expression correlates with poorer survival outcomes in LUAD patients but not in other NSCLC subtypes. Genetic modulation of\n                    <jats:italic>RKIP<\/jats:italic>\n                    expression in LUAD cell lines demonstrated that its overexpression reduced migration, spheroid integrity, and suppressed tumor growth, whereas RKIP knockout had opposite effects, particularly\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Expression profiling showed that RKIP overexpression impacts the activation of mitogen\u2010activated protein kinase (MAPK), RAC serine\/threonine\u2010protein kinase (AKT), and signal transducer and activator of transcription 3 (STAT3) pathways, as well as processes related to extracellular matrix regulation and inflammatory responses. Importantly,\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    experiments demonstrated that RKIP overexpression sensitizes cells to anti\u2010EGFR treatments, whereas RKIP knockout diminished their sensitivity. Overall, our findings indicate that RKIP modulates LUAD progression and response to EGFR\u2010targeted therapies, although its clinical value as a biomarker requires further validation. These findings highlight RKIP's potential in overcoming therapeutic resistance and the need for further investigation into its regulatory mechanisms.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70096","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T16:38:49Z","timestamp":1753720729000},"page":"3205-3222","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>RKIP<\/scp>\n                    overexpression reduces lung adenocarcinoma aggressiveness and sensitizes cells to\n                    <scp>EGFR<\/scp>\n                    \u2010targeted therapies"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9760-7605","authenticated-orcid":false,"given":"Ana","family":"Raquel\u2010Cunha","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine University of Minho  Braga Portugal"},{"name":"ICVS\/3Bs\u2010PT Government Associate Laboratory  Braga\/Guimar\u00e3es Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine University of Minho  Braga Portugal"},{"name":"ICVS\/3Bs\u2010PT Government Associate Laboratory  Braga\/Guimar\u00e3es Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui F.","family":"Marques","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine University of Minho  Braga Portugal"},{"name":"ICVS\/3Bs\u2010PT Government Associate Laboratory  Braga\/Guimar\u00e3es Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia","family":"Font\u00e3o","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine University of Minho  Braga Portugal"},{"name":"ICVS\/3Bs\u2010PT Government Associate Laboratory  Braga\/Guimar\u00e3es Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Cardoso\u2010Carneiro","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine University of Minho  Braga Portugal"},{"name":"ICVS\/3Bs\u2010PT Government Associate Laboratory  Braga\/Guimar\u00e3es Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Mendes","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine University of Minho  Braga Portugal"},{"name":"ICVS\/3Bs\u2010PT Government Associate Laboratory  Braga\/Guimar\u00e3es Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela N. 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