PMID- 31659178
OWN - NLM
STAT- MEDLINE
DCOM- 20201028
LR  - 20210110
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Oct 28
TI  - Identification of a novel synthetic lethal vulnerability in non-small cell lung 
      cancer by co-targeting TMPRSS4 and DDR1.
PG  - 15400
LID - 10.1038/s41598-019-51066-3 [doi]
LID - 15400
AB  - 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.
FAU - Villalba, Maria
AU  - Villalba M
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain.
AD  - Department of Pathology, Anatomy and Physiology, School of Medicine, University 
      of Navarra, Pamplona, Spain.
AD  - CIBERONC, ISC-III, Madrid, Spain.
FAU - Redin, Esther
AU  - Redin E
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain.
AD  - Department of Pathology, Anatomy and Physiology, School of Medicine, University 
      of Navarra, Pamplona, Spain.
FAU - Exposito, Francisco
AU  - Exposito F
AUID- ORCID: 0000-0002-5406-0768
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain.
AD  - Department of Pathology, Anatomy and Physiology, School of Medicine, University 
      of Navarra, Pamplona, Spain.
AD  - CIBERONC, ISC-III, Madrid, Spain.
FAU - Pajares, Maria Jose
AU  - Pajares MJ
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain.
AD  - Department of Pathology, Anatomy and Physiology, School of Medicine, University 
      of Navarra, Pamplona, Spain.
AD  - CIBERONC, ISC-III, Madrid, Spain.
FAU - Sainz, Cristina
AU  - Sainz C
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain.
FAU - Hervas, David
AU  - Hervas D
AUID- ORCID: 0000-0003-0635-4961
AD  - Data Science, Bioestatistics and Bioinformatics, Health Research Institute La Fe, 
      Valencia, Spain.
FAU - Guruceaga, Elizabeth
AU  - Guruceaga E
AD  - Bioinformatics Platform, Center for Applied Medical Research (CIMA), University 
      of Navarra, Pamplona, Spain.
FAU - Diaz-Lagares, Angel
AU  - Diaz-Lagares A
AD  - CIBERONC, ISC-III, Madrid, Spain.
AD  - Translational Medical Oncology (Oncomet), Health Research Institute of Santiago 
      (IDIS), University Clinical Hospital of Santiago (CHUS), Santiago de Compostela, 
      Spain.
FAU - Cirauqui, Cristina
AU  - Cirauqui C
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain.
FAU - Redrado, Miriam
AU  - Redrado M
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain.
FAU - Valencia, Karmele
AU  - Valencia K
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain.
AD  - CIBERONC, ISC-III, Madrid, Spain.
AD  - Department of Biochemistry and Genetics, School of Science, University of 
      Navarra, Pamplona, Spain.
FAU - de Andrea, Carlos
AU  - de Andrea C
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain.
AD  - Department of Pathology, Anatomy and Physiology, School of Medicine, University 
      of Navarra, Pamplona, Spain.
AD  - CIBERONC, ISC-III, Madrid, Spain.
FAU - Jantus-Lewintre, Eloisa
AU  - Jantus-Lewintre E
AUID- ORCID: 0000-0001-7395-4380
AD  - CIBERONC, ISC-III, Madrid, Spain.
AD  - Molecular Oncology Laboratory, General University Hospital Research Foundation, 
      Valencia, Spain.
AD  - Department of Biotechnology, Universitat Politecnica de Valencia, Valencia, 
      Spain.
FAU - Camps, Carlos
AU  - Camps C
AD  - CIBERONC, ISC-III, Madrid, Spain.
AD  - Molecular Oncology Laboratory, General University Hospital Research Foundation, 
      Valencia, Spain.
AD  - Department of Medicine Universitat de Valencia, Valencia, Spain.
FAU - Lopez-Lopez, Rafael
AU  - Lopez-Lopez R
AD  - CIBERONC, ISC-III, Madrid, Spain.
AD  - Translational Medical Oncology (Oncomet), Health Research Institute of Santiago 
      (IDIS), University Clinical Hospital of Santiago (CHUS), Santiago de Compostela, 
      Spain.
FAU - Lahoz, Agustin
AU  - Lahoz A
AD  - Biomarkers and Precision Medicine Unit, Health Research Institute la Fe, 
      Valencia, Spain.
FAU - Montuenga, Luis
AU  - Montuenga L
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain.
AD  - Department of Pathology, Anatomy and Physiology, School of Medicine, University 
      of Navarra, Pamplona, Spain.
AD  - CIBERONC, ISC-III, Madrid, Spain.
FAU - Pio, Ruben
AU  - Pio R
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain.
AD  - CIBERONC, ISC-III, Madrid, Spain.
AD  - Department of Biochemistry and Genetics, School of Science, University of 
      Navarra, Pamplona, Spain.
FAU - Sandoval, Juan
AU  - Sandoval J
AD  - Biomarkers and Precision Medicine Unit, Health Research Institute la Fe, 
      Valencia, Spain. epigenomica@iislafe.es.
FAU - Calvo, Alfonso
AU  - Calvo A
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, Pamplona, Spain. acalvo@unav.es.
AD  - Department of Pathology, Anatomy and Physiology, School of Medicine, University 
      of Navarra, Pamplona, Spain. acalvo@unav.es.
AD  - CIBERONC, ISC-III, Madrid, Spain. acalvo@unav.es.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191028
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Membrane Proteins)
RN  - EC 2.7.10.1 (DDR1 protein, human)
RN  - EC 2.7.10.1 (Discoidin Domain Receptor 1)
RN  - EC 3.4.21.- (Serine Endopeptidases)
RN  - EC 3.4.21.- (TMPRSS4 protein, human)
RN  - Q20Q21Q62J (Cisplatin)
RN  - RBZ1571X5H (Dasatinib)
SB  - IM
MH  - Adenocarcinoma/*genetics/pathology
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Biomarkers, Tumor/*genetics
MH  - Cell Line, Tumor
MH  - Cisplatin/toxicity
MH  - DNA Methylation
MH  - Dasatinib/toxicity
MH  - Discoidin Domain Receptor 1/*genetics
MH  - Drug Resistance, Neoplasm
MH  - Humans
MH  - Lung Neoplasms/*genetics/pathology
MH  - Membrane Proteins/*genetics
MH  - Mice
MH  - Promoter Regions, Genetic
MH  - Serine Endopeptidases/*genetics
MH  - *Synthetic Lethal Mutations
PMC - PMC6817908
COIS- The authors declare no competing interests.
EDAT- 2019/10/30 06:00
MHDA- 2020/10/29 06:00
PMCR- 2019/10/28
CRDT- 2019/10/30 06:00
PHST- 2019/01/11 00:00 [received]
PHST- 2019/07/29 00:00 [accepted]
PHST- 2019/10/30 06:00 [entrez]
PHST- 2019/10/30 06:00 [pubmed]
PHST- 2020/10/29 06:00 [medline]
PHST- 2019/10/28 00:00 [pmc-release]
AID - 10.1038/s41598-019-51066-3 [pii]
AID - 51066 [pii]
AID - 10.1038/s41598-019-51066-3 [doi]
PST - epublish
SO  - Sci Rep. 2019 Oct 28;9(1):15400. doi: 10.1038/s41598-019-51066-3.