Clearing the TRAIL for cancer therapy

The death receptor ligand TRAIL has shown remarkable promise as an anticancer agent. However, TRAIL signaling also activates NF-kappa B, which induces the antiapoptotic regulators Mcl-1 and cIAP2, thus compromising its efficacy. In this issue of Cancer Cell, EI-Deiry and colleagues explore pathways that disrupt TRAIL-induced survival signaling and show that the Myc oncoprotein and the Raf kinase inhibitor Sorafenib sensitize otherwise TRAIL-resistant colon cancer cells by effectively reducing NF-kappa B-mediated transcription of Mcl-1. These findings suggest that combining TRAIL with agents that disrupt NF-kappa B regulation or binding or those that directly destabilize or disable Mcl-1 will have therapeutic benefit.