Identification of 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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Detalles Bibliográficos
Autores: Villalba-Esparza, M. (María)|||/items/203ea86e-61c4-420d-b975-6c7d647bc07e, Redín, E. (Esther)|||/items/be984926-e359-4646-9a53-58a7dfcf723d, Expósito, F. (Francisco)|||/items/df090510-428a-427f-91b4-4e9410bdaf27, Pajares, M.J. (María José)|||/items/fd08bca6-05af-4e13-95b9-be62f8295285, Sainz, C. (Cristina)|||/items/8e37fd4c-1c10-4976-a463-5666bb1995ac, Hervas, D. (D.)|||/items/4c0ecb46-ebfd-4629-9a7b-d78a2cf944ee, Guruceaga-Martínez, E. (Elizabeth)|||/items/71d8df8b-4fab-4004-a38e-4057dddc85b2, Diaz-Lagares, A. (Ángel)|||/items/3697306a-f4e8-4bf2-b776-d5eaa2eb48ac, Cirauqui, C. (Cristina)|||/items/b165cbc3-ff90-47ae-8d65-0e960d9fde6c, Redrado, M. (Miriam)|||/items/a29b6f51-e97e-4d0a-816f-c3c3019ee27a, Valencia, K. (Karmele)|||/items/bf771eab-81c1-4221-80f5-87713ad5e51f, Andrea, C.E. (Carlos Eduardo) de|||/items/e487698b-8d56-4c3e-8cba-40e33c78083a, Jantus-Lewintre, E. (Eloisa)|||/items/efd6c26d-c4fa-48fc-b7ba-040557d28e4a, Camps, C. (Carlos)|||/items/3f670e07-35ed-47eb-b769-ed71635a78dc, López-López, R. (Rafael)|||/items/98158916-80af-45e6-a407-51462ebf3a77, Lahoz, A. (Agustín)|||/items/baa956ab-e620-4562-bec5-2a0e4451993a, Montuenga-Badia, L.M. (Luis M.)|||/items/4c999705-b2c9-45ac-ba13-3f18594ae596, Pio, R. (Rubén)|||/items/d5c409b3-dbed-4f0c-8bad-94c31e0e5a95, Sandoval, J. (Juan)|||/items/15e9a801-000b-48f9-8cc5-6747af534849, Calvo-González, A. (Alfonso)|||/items/ac176653-87d5-476b-b2b9-ade455cfa6de
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/62412
Acceso en línea:https://hdl.handle.net/10171/62412
Access Level:acceso abierto
Palabra clave:Materias Investigacion::Ciencias de la Salud::Oncología
Anatomía patológica
Descripción
Sumario: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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