RKIP overexpression reduces lung adenocarcinoma aggressiveness and sensitizes cells to EGFR ‐targeted therapies
Year: 2025
Type: article
Abstract: Lung adenocarcinoma (LUAD), the most common subtype of non-small-cell lung cancer (NSCLC), is often driven by mutations, particularly in epidermal growth factor receptor (EGFR), that guide targeted therapy choices. However, resistance to these treatments remains a major clinical challenge. Raf kinase inhibitory protein (RKIP), encoded by the PEBP1 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-targeted therapies. In silico analyses revealed that lower RKIP mRNA expression correlates with poorer survival outcomes in LUAD patients but not in other NSCLC subtypes. Genetic modulation of RKIP expression in LUAD cell lines demonstrated that its overexpression reduced migration, spheroid integrity, and suppressed tumor growth, whereas RKIP knockout had opposite effects, particularly in vivo. Expression profiling showed that RKIP overexpression impacts the activation of mitogen-activated protein kinase (MAPK), RAC serine/threonine-protein 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, in vitro and in vivo experiments demonstrated that RKIP overexpression sensitizes cells to anti-EGFR treatments, whereas RKIP knockout diminished their sensitivity. Overall, our findings indicate that RKIP modulates LUAD progression and response to EGFR-targeted 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.
Source: Molecular Oncology
Institutions: University of Minho, Hospital de Câncer de Barretos
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,300
Awards: ICVS/3B’s - Laboratório Associado, Instituto de Ciências da Vida e da Saúde / Grupo de Investigação em Biomateriais, Biodegradaveis e Biomiméticos, G1060885716, G1778465840, Sem título, G2085696165, Unraveling the role of RKIP protein in the modulation of solid tumors microenvironment, ICVS/3B’s - Laboratório Associado, Instituto de Ciências da Vida e da Saúde / Grupo de Investigação em Biomateriais, Biodegradaveis e Biomiméticos, G2569627776, G3525276842, ICVS/3B’s - Laboratório Associado, Instituto de Ciências da Vida e da Saúde / Grupo de Investigação em Biomateriais, Biodegradaveis e Biomiméticos, G4724859719, RKIP protein as a novel predictor of EGFR targeted therapy response in lung cancer, Sem título, Raf Kinase Inhibitory Protein (RKIP) as a modulator of tumor microenvironment and therapy response in cervical cancer, G6630026919, G6940391506, G7274947606, G7420908265, G7661467656, Role of RKIP protein in the modulation of immune checkpoint blockade in cervical cancer, G8471131429
OpenAlex ID: W4412702017