TRAIL receptor targeting therapies for non-small cell lung cancer: Current status and perspectives

Stegehuis, J.H.; de Wilt, L.H.A.M.; de Vries, E.G.E.; Groen, H.J.; de Jong, S.; Kruyt, F.A.E.

doi:10.1016/j.drup.2009.11.001

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Volume 13, Issue 1 , Pages 2-15, February 2010

TRAIL receptor targeting therapies for non-small cell lung cancer: Current status and perspectives

J.H. Stegehuis
- Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
- Both authors contributed equally to this work.
L.H.A.M. de Wilt
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
- Both authors contributed equally to this work.
E.G.E. de Vries
- Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
H.J. Groen
- Department of Pulmonology, University Medical Center Groningen, Groningen, The Netherlands
S. de Jong
- Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
F.A.E. Kruyt
- Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
- Corresponding author. Tel.: +31 50 3615531; fax: +31 50 3614862.

Received 8 November 2009; accepted 25 November 2009. published online 28 December 2009.

Abstract

Non-small cell lung cancer (NSCLC) is a common and often fatal malignancy, diagnosed at an advanced stage in more than half of the cases. Chemo-resistance remains a major problem in the treatment of NSCLC patients with conventional chemotherapeutic agents. Therefore main research efforts are focused on the development of novel targeted agents. In this review we provide an overview on the use of TNF-related apoptosis-inducing ligand (TRAIL) receptor targeting agents in NSCLC models and in early clinical studies. Different TRAIL receptor targeting agents are available which have been tested in NSCLC models and some were tested in the clinic. The efficacy of these drugs as single agents in NSCLC models is discussed as well as different mechanisms of resistance that are found in NSCLC cell lines. In order to maximize sensitivity to TRAIL receptor targeting drugs, combined use with other drugs is of interest. The current status of tested combinations of TRAIL receptor targeting agents with other therapeutics, such as classical cytotoxics, Bcl-2 family targeting agents, proteasome inhibitors, EGFR inhibitors, histone deacetylase inhibitors and COX-2 inhibitors as well as their mechanisms in preclinical studies are discussed. Clinical studies on TRAIL targeted therapies in which NSCLC patients were included are discussed and future perspectives are considered.

Keywords: TRAIL, Death receptors, NSCLC, Apoptosis, TRAIL resistance, Cancer therapy, Bortezomib