title: Targeting TRAIL towards the clinic.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand or Apo2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis upon binding to its death domain-containing transmembrane receptors. The preferential toxicity of TRAIL to cancer cells and the sparing of normal cells make it an ideal cancer therapeutic agent. TRAIL induces apoptosis via the extrinsic death receptor apoptotic pathway and activates the JNK, ERK, Akt and NF-κB signaling cascades. However, not all cancer cells are sensitive to TRAIL therapy. This may limit its efficacy in the clinic, although ways have already been identified to overcome resistance by combining TRAIL with chemotherapeutic and other biological agents. This review focuses on TRAIL receptor-targeting as anticancer therapy, the apoptotic signaling pathways induced by TRAIL receptors, the prognostic implications of TRAIL receptor expression and modulation by combination therapies. The mechanisms of TRAIL resistance and strategies to overcome drug resistance will also be addressed. Finally, the progress of TRAIL and DR4/DR5-specific agonistic antibodies in clinical trials and the development of new receptor-selective TRAIL variants are discussed including future directions for apoptosis inducing therapy.
authors.affiliation: Cancer Research and Therapy Center, University of Texas Health Science Center, San Antonio, TX 78229, USA. mahalingam@uthscsa.edu
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.forename: Corina N A M
authors.initials: CN
authors.lastname: Oldenhuis
authors.forename: Eva
authors.initials: E
authors.lastname: Szegezdi
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: Steven
authors.initials: S
authors.lastname: de Jong
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53