Journal Article

The TRAIL apoptotic pathway in cancer onset, progression and therapy

Johnstone, Ricky W., Smyth, Mark J., Frew, Ailsa J.

2008

Overview

Key Points Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent stimulator of apoptosis, and tumour cells are significantly more sensitive to TRAIL-induced apoptosis than normal cells. Although the molecular basis for the tumour-selective activity of TRAIL remains to be fully defined, the TRAIL pathway is an attractive therapeutic target for the treatment of cancer. In addition to triggering a pro-apoptotic signal through activation of caspases, TRAIL can activate diverse intracellular signalling pathways involving NFκB, phosphoinositoide 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) family proteins that can stimulate cell survival and proliferation. TRAIL is an important immune effector molecule in the surveillance and elimination of developing tumours. Moreover, genetic lesions in various components of the TRAIL pathway have been found in human tumour samples, suggesting that inactivation of the TRAIL pathway and/or escape from TRAIL-mediated immunosurveillance might have an important role in tumour onset and progression. In preclinical trials, recombinant forms of TRAIL and agonistic anti-TRAIL receptor antibodies can have single-agent activity against TRAIL-sensitive tumour cells in vitro and in vivo . These agents can synergize with chemotherapeutic drugs and novel molecular therapeutic agents to more effectively kill TRAIL-sensitive tumour cells and TRAIL-resistant tumours. Early-phase clinical trials using recombinant TRAIL and agonistic anti-TRAIL receptor antibodies indicate that these agents can be delivered safely and are generally well-tolerated. Although some objective anti-tumour responses have been reported with these agents as monotherapies, they probably hold greater promise for further clinical development when used in combination with other cancer treatments. Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors (TRAILR1 and TRAILR2) are promising targets for cancer therapy: both recombinant TRAIL and monoclonal antibodies that target these receptors have entered clinical trials. How are these agents faring? What are the current stumbling blocks? Triggering of tumour cell apoptosis is the foundation of many cancer therapies. Death receptors of the tumour necrosis factor (TNF) superfamily have been largely characterized, as have the signals that are generated when these receptors are activated. TNF-related apoptosis-inducing ligand (TRAIL) receptors (TRAILR1 and TRAILR2) are promising targets for cancer therapy. Herein we review what is known about the molecular control of TRAIL-mediated apoptosis, the role of TRAIL in carcinogenesis and the potential therapeutic utility of recombinant TRAIL and agonistic antibodies against TRAILR1 and TRAILR2.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Apoptosis / Biomedical and Life Sciences / Biomedicine / Cancer cells / Cancer Research / Cellular signal transduction / Control / Disease Models, Animal / Genetic Predisposition to Disease / Health aspects / Humans / Mice / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - metabolism / Receptors, Death Domain - antagonists & inhibitors / Receptors, Death Domain - metabolism / Receptors, TNF-Related Apoptosis-Inducing Ligand - antagonists & inhibitors / Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism / Recombinant Proteins - therapeutic use / review-article / Signal Transduction / TNF-Related Apoptosis-Inducing Ligand - agonists / TNF-Related Apoptosis-Inducing Ligand - metabolism / TNF-Related Apoptosis-Inducing Ligand - therapeutic use / Tumor necrosis factor