Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy

Clinical trials testing activators of tumour necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) signalling in cancer have not met expectations. This Review discusses new insights that might explain clinical failure, but also provide the basis for harnessing TRAIL-Rs for cancer therapy. The discovery that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of cancer cells without causing toxicity in mice has led to the in-depth study of pro-apoptotic TRAIL receptor (TRAIL-R) signalling and the development of biotherapeutic drug candidates that activate TRAIL-Rs. The outcome of clinical trials with these TRAIL-R agonists has, however, been disappointing so far. Recent evidence indicates that many cancers, in addition to being TRAIL resistant, use the endogenous TRAIL–TRAIL-R system to their own advantage. However, novel insight on two fronts — how resistance of cancer cells to TRAIL-based pro-apoptotic therapies might be overcome, and how the pro-tumorigenic effects of endogenous TRAIL might be countered — gives reasonable hope that the TRAIL system can be harnessed to treat cancer. In this Review we assess the status quo of our understanding of the biology of the TRAIL–TRAIL-R system — as well as the gaps therein — and discuss the opportunities and challenges in effectively targeting this pathway.