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

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. •X-Ray crystallography reveals netrin-1 interaction domain with its receptor UNC5•An antibody blocking netrin-1 and UNC5 interaction triggers tumor cell death•Epigenetic silencing of UNC5 death signaling is frequent in human lung tumors•Combining netrin-1 interference with epidrugs is a promising therapeutic approach Grandin et al. identify netrin-1/UNC5H2 interaction domains and generate an anti-netrin-1 antibody that disrupts this interaction and triggers death of netrin-1-expressing tumor cells. They show that epidrugs can sensitize tumor cells expressing no or low netrin-1 to this antibody by inducing netrin-1 expression.