Overcoming Cancer Cell Resistance To Death Receptor Targeted Therapies

Death receptors (DRs) are promising targets for cancer therapies because of their ability to induce apoptosis in cancer cells. These receptors are characterized by an intracellular death domain, which transmits a death signal from their cognate ligands, including TNF-related apoptosis inducing ligand (TRAIL). Currently, multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to its receptors DR4 and DR5. Although the products have shown a tolerated safety profile in the completed phase 1 studies, a large number of cancer cell lines are found to be resistant to these agents, raising a concern about their clinical efficacy. This review provides an update of recent advances in understanding the molecular mechanisms involved in cancer cell resistance to DR4/DR5 targeted therapies. This information will be further discussed with respect to combinational strategies to overcome or bypass resistance mechanisms towards a better treatment outcome.