Scientific publications

Identification of a novel synthetic lethal vulnerability in non-small cell lung cancer by co-targeting TMPRSS4 and DDR1

Oct 28, 2019 | Magazine: Scientific Reports

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


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.

Our authors

Esther Redín Resano
Francisco Expósito Rincón
Cristina Sainz
Laboratory technician Solid Tumor Research Program
Elizabet Guruceaga Martínez
Bioinformatics Research Technician Bioinformatics Platform
Dr. Miriam Redrado Jordán
Laboratory technician Solid Tumor Research Program