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
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.
CITA DEL ARTÍCULO Sci Rep. 2019 Oct 28;9(1):15400. doi: 10.1038/s41598-019-51066-3.