Scientific publications
- [SOLID TUMOR]
- [LUNGSEARCH: LUNG CANCER SCREENING, EARLY DETECTION, BIOMARKERS AND NEW THERAPEUTIC TARGETS ]
- [BIOINFORMATICS]
Identification of a novel synthetic lethal vulnerability in non-small cell lung cancer by co-targeting TMPRSS4 and DDR1
Maria Villalba, Esther Redin, Francisco Exposito, Maria Jose Pajares, Cristina Sainz, David Hervas, Elizabeth Guruceaga, Angel Diaz-Lagares, Cristina Cirauqui, Miriam Redrado, Karmele Valencia, Carlos de Andrea, Eloisa Jantus-Lewintre, Carlos Camps, Rafael Lopez-Lopez, Agustin Lahoz, Luis Montuenga, Ruben Pio, Juan Sandoval, Alfonso Calvo
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.
CITATION Sci Rep. 2019 Oct 28;9(1):15400. doi: 10.1038/s41598-019-51066-3.
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Our authors
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![Cristina Sáiz. Programa Tumores Sólidos. Cima](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/programas-verticales/tumores-solidos/cristina-saiz-zubieta/jcr:content/cristina-saiz-zubieta.jpg)
![Elisabet Guruceaga. Programa Biología Computacional. Cima](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/programas-transversales/biologia-computacional/elisabet-guruceaga-martinez/jcr:content/elisabet-guruceaga-martinez.jpg)
![Miriam Redrado. Programa Tumores Sólidos. Cima](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/programas-verticales/tumores-solidos/miriam-redrado-jordan/jcr:content/miriam-redrado-jordan.jpg)
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