TRAIL of Hope Meeting Resistance in Cancer

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis selectively via its interaction with the death receptors TRAILR1/DR4 and TRAILR2/DR5 in a wide range of cancers, while sparing normal cells. Despite its tremendous potential for cancer therapeutics, the translation of TRAIL into the clinic has been confounded by TRAIL-resistant cancer populations. We discuss different molecular mechanisms underlying TRAIL-mediated apoptosis and resistance to TRAIL. We also discuss the successes and failures of recent preclinical and clinical studies of TRAIL-induced apoptosis, and current attempts to overcome TRAIL resistance, and we provide a perspective for improving the prospects of future clinical implementation.