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)
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.