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Structural decoding of the Netrin-1/UNC5 interaction and its therapeutical implications in cancers

  • Articles in SCI Journals
  • Apr, 2016

Grandin, M., Meier, M., Delcros, J.G., Nikodemus, D., Reuten, R., Patel, T.R., Goldschneider, D., Orriss, G., Krahn, N., Boussouar, A., Abes, R., Dean, Y., Neves, D., Bernet, A., Depil, S., Schneiders, F., Poole, K., Dante, R., Koch, M., Mehlen, P. & Stetefeld, J. (2016) Structural decoding of the Netrin-1/UNC5 interaction and its therapeutical implications in cancers.

Cancer Cell, 29(2), 173-185. DOI:10.1016/j.ccell.2016.01.001 (IF2015 23,214; Q1 Cell Biology)
Summary:

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.


http://www.cell.com/cancer-cell/abstract/S1535-6108(16)00029-5