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Identification of a novel synthetic lethal vulnerability in non-small cell lung cancer by co-targeting TMPRSS4 and DDR1
dc.contributor.author | Villalba, M. | |
dc.contributor.author | Redin, E. | |
dc.contributor.author | Exposito, F. | |
dc.contributor.author | Pajares, M. J. | |
dc.contributor.author | Sainz, C. | |
dc.contributor.author | Hervas, D. | |
dc.contributor.author | Guruceaga, E. | |
dc.contributor.author | Díaz Lagares, Ángel | |
dc.contributor.author | Cirauqui, C. | |
dc.contributor.author | Redrado, M. | |
dc.contributor.author | Valencia, K. | |
dc.contributor.author | de Andrea, C. | |
dc.contributor.author | Jantus-Lewintre, E. | |
dc.contributor.author | Camps, C. | |
dc.contributor.author | López López, Rafael | |
dc.contributor.author | Lahoz, A. | |
dc.contributor.author | Montuenga, L. | |
dc.contributor.author | Pio, R. | |
dc.contributor.author | Sandoval, J. | |
dc.contributor.author | Calvo, A. | |
dc.date.accessioned | 2021-10-15T11:01:15Z | |
dc.date.available | 2021-10-15T11:01:15Z | |
dc.date.issued | 2019 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.other | https://www.ncbi.nlm.nih.gov/pubmed/31659178 | |
dc.identifier.other | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817908/pdf/41598_2019_Article_51066.pdf | |
dc.identifier.uri | http://hdl.handle.net/20.500.11940/15507 | |
dc.description.abstract | Finding novel targets in non-small cell lung cancer (NSCLC) is highly needed and identification of synthetic lethality between two genes is a new approach to target NSCLC. We previously found that TMPRSS4 promotes NSCLC growth and constitutes a prognostic biomarker. Here, through large-scale analyses across 5 public databases we identified consistent co-expression between TMPRSS4 and DDR1. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down (KD) cells, but not single KD cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and a larger number of cells in apoptosis. Moreover, double KD cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in double KD-injected mice. In conclusion, we have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4. | |
dc.rights | Atribución 4.0 Internacional | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.title | Identification of a novel synthetic lethal vulnerability in non-small cell lung cancer by co-targeting TMPRSS4 and DDR1 | |
dc.type | Artigo | es |
dc.authorsophos | López López, Rafael | |
dc.authorsophos | Díaz Lagares, Ángel | |
dc.identifier.doi | 10.1038/s41598-019-51066-3 | |
dc.identifier.pmid | 31659178 | |
dc.identifier.sophos | 31038 | |
dc.issue.number | 1 | |
dc.journal.title | Scientific Reports | |
dc.organization | Servizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::EOXI de Santiago de Compostela - Complexo Hospitalario Universitario de Santiago de Compostela::Oncoloxía médica | |
dc.organization | Servizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS) | |
dc.page.initial | 15400 | es |
dc.rights.accessRights | openAccess | |
dc.subject.keyword | CHUS | |
dc.subject.keyword | IDIS | |
dc.typefides | Artículo Científico (incluye Original, Original breve, Revisión Sistemática y Meta-análisis) | |
dc.typesophos | Artículo Original | |
dc.volume.number | 9 |