TRAIL receptor signaling and therapeutics

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells by engaging specific death receptors, TRAIL-R1 and TRAIL-R2, while having low toxicity towards normal cells. There is interest in cancer therapy inducing cell death by activation of the death-receptor-mediated apoptotic pathway while avoiding decoy-receptor-mediated neutralization of the signal. This has led to the development of a number of receptor-specific TRAIL-variants and agonistic antibodies. Some of these soluble recombinant TRAIL and agonist antibodies targeting TRAIL-R1 and/or TRAIL-R2 are progressing in clinical trials. In addition, TRAIL-resistant tumors can be sensitized to TRAIL by a combination of TRAIL or agonistic antibodies with chemotherapeutic agents, targeted small molecules or irradiation.Recent advances in developing TRAIL or its agonist receptor antibodies in cancer therapy. We also discuss combination therapies in overcoming TRAIL resistance in cancer cells.Knowledge of current clinical trials, the promise and obstacles in the future development of therapies affecting TRAIL signaling pathways.Cancer therapeutics targeting the TRAIL/TRAIL receptor signaling pathway hold great promise for molecularly targeted pro-apoptotic anti-cancer therapy.