Redirecting cancer kinase signaling: A novel rewiring of Bcr/Abl and PKC Beta II
Hoekstra, David Arthur, II
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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 βII (PKCβII) 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 PKCβII 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 PKCβII 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.