TRAIL receptor-targeted therapeutics: resistance mechanisms and strategies to avoid them.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors are attractive therapeutic targets in cancer because agents that activate these receptors directly induce tumor cell apoptosis and have low toxicity to normal tissues. Consequently, several different drugs that target these receptors (recombinant TRAIL and various agonistic antibodies that activate one of the two TRAIL receptors) have been developed and are being tested in human clinical trials. However, in vitro and in vivo data suggest that resistance to these agents may limit their clinical effectiveness. In this review, we discuss recent findings about some of the ways these resistance mechanisms arise, potential biomarkers to identify TRAIL resistance in patients (Six1, GALNT14, XIAP, certain microRNAs) and potential ways to circumvent resistance and resensitize tumors.
Thorburn
Andrew
A
Department of Pharmacology, University of Colorado Denver, School of Medicine, Aurora, CO 80010, USA. Andrew.Thorburn@uchsc.edu
Behbakht
Kian
K
Ford
Heide
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000235:genetics / Q000502:physiology
D000970:Antineoplastic Agents; D053221:TNF-Related Apoptosis-Inducing Ligand