Sensitizing Tumor Cells by Targeting Death Receptor Signaling Inhibitors

Abstract

Therapies aimed at death receptor signaling using FasL or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as agonists have become an active area of research in the development of novel anticancer therapies. Systemic delivery of FasL causes hepatotoxicity, limiting its use to local administration (1). In contrast, preclinical studies with TRAIL show that systemic delivery of the soluble form is well tolerated in nonhuman primates (2, 3, 4). Exposure of normal human cells to TRAIL was also well tolerated, whereas TRAIL induced apoptosis in numerous malignant cell lines that were analyzed in initial studies (2,5,6). However, as more malignant cell lines and fresh tumor explants were examined, it became clear that TRAIL also fails to induce significant apoptosis in many transformed cells (7, 8, 9, 10, 11). Numerous studies have been undertaken to understand mechanisms of death receptor ligand resistance, and strategies to enhance sensitivity or overcome resistance have been devised. In this chapter the role, function, and regulation of the death receptor signaling pathway inhibitors, how they can be targeted therapeutically, and the implications for future cancer therapies will be discussed.