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