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Cancer Cell. 2016 Feb 8;29(2):173-85. doi: 10.1016/j.ccell.2016.01.001.

Structural Decoding of the Netrin-1/UNC5 Interaction and its Therapeutical Implications in Cancers.

Author information

1
Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
2
Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, MB RT3 2N2, Canada.
3
Center for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, University of Cologne, 50931 Cologne, Germany; Centre for Ecology, Evolution and Environmental Changes, Faculdade de Ciências, Universidade de Lisboa, Lisbon 1749-016, Portugal.
4
Center for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, University of Cologne, 50931 Cologne, Germany.
5
Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, MB RT3 2N2, Canada; Department of Microbiology, University of Manitoba, 144 Dysart Road, Winnipeg, MB RT3 2N2, Canada.
6
Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France; Netris Pharma, Centre Léon Bérard, 69008 Lyon, France.
7
Netris Pharma, Centre Léon Bérard, 69008 Lyon, France.
8
Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Straβe 10, Berlin 13092, Germany.
9
Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France. Electronic address: patrick.mehlen@lyon.unicancer.fr.
10
Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, MB RT3 2N2, Canada. Electronic address: jorg.stetefeld@ad.manitoba.ca.

Abstract

Netrin-1 has been shown to be up-regulated in a fraction of human cancers as a mechanism to allow these tumors to escape the pro-apoptotic activity of some of its main dependence receptors, the UNC5 homologs (UNC5H). Here we identify the V-2 domain of netrin-1 to be important for its interaction with the Ig1/Ig2 domains of UNC5H2. We generate a humanized anti-netrin-1 antibody that disrupts the interaction between netrin-1 and UNC5H2 and triggers death of netrin-1-expressing tumor cells in vitro. We also present evidence that combining the anti-netrin-1 antibody with epidrugs such as decitabine could be effective in treating tumors showing no or modest netrin-1 expression. These results support that this antibody is a promising drug candidate.

PMID:
26859457
DOI:
10.1016/j.ccell.2016.01.001
[Indexed for MEDLINE]
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