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

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 analyse...

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Authors: Villalba, M., Redin, E., Exposito, F., Pajares, M. J., Sainz, C., Hervas, D., Guruceaga, E., Díaz Lagares, Ángel, Cirauqui, C., Redrado, M., Valencia, K., de Andrea, C., Jantus-Lewintre, E., Camps, C., López López, Rafael, Lahoz, A., Montuenga, L., Pio, R., Sandoval, J., Calvo, A.
Format: article
Publication Date:2019
Country:España
Institution:Servizo Galego de Saúde (SERGAS)
Repository:RUNA. Repositorio da Consellería de Sanidade e Sergas
OAI Identifier:oai:runa.sergas.gal:20.500.11940/15507
Online Access:https://www.ncbi.nlm.nih.gov/pubmed/31659178
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817908/pdf/41598_2019_Article_51066.pdf
http://hdl.handle.net/20.500.11940/15507
Access Level:Open access
Keyword:CHUS
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Summary: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.

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