| Mutations in cancer very frequently cause aberrant signal transduction. This dysfunctional signaling blocks apoptotic and differentiation pathways, activates proliferative and survival pathways, and plays a central role in cancer survival. While small molecule kinase inhibitors have been successful in blocking oncogenic kinase signaling and attenuating disease, resistance to this therapy remains a significant obstacle. Instead of blocking oncogenic kinase signaling, an alternative approach would be to redirect proliferative signal transduction into an unrelated apoptotic/differentiation signal transduction cascade. To this end we have generated a rewired Protein Kinase C isoform betaII (PKCbetaII) that is activated by unrelated oncogenic tyrosine kinase Bcr-Abl, through the incorporation of Bcr-Abl's substrate target motif. The activation of the mutant PKCbetaII protein by Bcr-Abl is sufficient to redirect proliferative signaling into apoptotic and differentiation signaling in Bcr-Abl+ cells, while leaving Bcr-Abl- cells unaffected. In vivo, expression of mutant PKCbetaII constructs delays tumor growth and confers a survival advantage in mice implanted with Bcr-Abl + tumors. These findings are the first to demonstrate that it is possible to redirect an oncogenic signaling pathway into an unrelated and deleterious signaling pathway, and provide a novel methodology for cancer therapeutics. |
