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

Abstract

Netrin-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-domain of netrin-to be important for its interaction with the Ig1/Ig2 domains of UNC5H2. We generate a humanized anti-netrin-antibody that disrupts the interaction between netrin-and UNC5H2 and triggers death of netrin-1-expressing tumor cells in vitro. We also present evidence that combining the anti-netrin-antibody with epidrugs such as decitabine could be effective in treating tumors showing no or modest netrin-expression. These results support that this antibody is a promising drug candidate. Grandin et al. identify netrin-1/UNC5H2 interaction domains and generate an anti-netrin-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-to this antibody by inducing netrin-expression.