Cancer Letters

Cancer Letters

Volume 332, Issue 2, 28 May 2013, Pages 359-368
Cancer Letters

Mini-review
Targeting apoptosis pathways in lung cancer

https://doi.org/10.1016/j.canlet.2010.09.012Get rights and content

Abstract

Lung cancer is a devastating disease with a poor prognosis. Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) represent different forms of lung cancer that are associated with distinct genetic causes and display different responses to therapy in the clinic. Whereas SCLC is often sensitive to chemotherapy at start of treatment, NSCLC are less chemo-sensitive. In NSCLC different histological subtypes are distinguished and increasing efforts are made to identify subtypes that respond to specific therapies, such as those harbouring epidermal growth factor receptor (EGFR) mutations that have benefit from treatment with EGFR inhibitors. Targeting of the apoptotic machinery represents another approach that aims to selectively kill cancer cells while sparing normal ones. Here we describe different ways that are currently explored to induce apoptosis in lung cancer cells, specifically pathways controlled by TNF-related apoptosis-inducing ligand (TRAIL), BCL-2 family members and apoptosis inhibitory proteins (IAPs). Preclinical studies are discussed and for some agents results from early clinical studies and future perspectives are considered.

Section snippets

Lung cancer

Lung cancer is the leading cause of cancer related deaths worldwide. It has been estimated that more than 1 million people die with it annually and approximately 1.4 millions are diagnosed per year, 12% of which are new cases [1]. Lung cancers are divided into small cell lung cancer (SCLC) which comprises of 15–20% of total lung cancer cases and remaining 80–85% are attributed to the non-small cell lung cancers (NSCLC). On the basis of histological characteristics NSCLC is further divided into

Apoptotic cell death

Apoptosis or programmed cell death is a physiological process that provides an effective, non-inflammatory way to remove redundant or damaged cells from tissues thereby securing tissue homeostasis [7]. Inhibition of apoptosis is considered as an essential step in tumorigenesis and is one of the hallmarks of cancer, allowing the survival of cells that accumulate oncogenic events that otherwise would have been removed by apoptosis [8]. A multitude of signals activated by variable triggers, such

Apoptosis as target for therapy

Standard cancer therapies such as chemotherapy and radiation eradicate tumor cells at least in part by indirectly activating the apoptotic machinery [17]. In this process the tumor suppressor p53 is an important effector that predominantly induces transcription-dependent mechanisms of apoptosis by upregulating pro-apoptotic genes such as PUMA, BAX and death receptors and subsequent activation of intrinsic and/or extrinsic apoptosis [18]. It is observed that around 50% of all types of lung

TRAIL receptor targeted therapy

Targeting of the TRAIL receptor signaling pathway is an attractive approach since it provides a direct apoptosis trigger that selectively kills tumor cells without harming normal cells [20]. Two membrane receptors mediate apoptosis, designated TRAIL-R1 (DR4) and TRAIL-R2 (DR5), whereas TRAIL-R3 (DcR1), -R4 (DcR2) and circulating osteoprotegerin (OPG) are non-functional decoy receptors that are able to sequester TRAIL causing suppression of apoptosis [21]. The mechanisms underlying the selective

BCL-2 targeted therapy

BCL-2 is frequently overexpressed in tumors and in lung cancer a meta-analysis has reported 76% and 35% in SCLC and NSCLC, respectively, of patients samples positive for BCL-2 [38]. Overexpression of anti-apoptotic BCL-2 family members is known to cause apoptosis and therapy resistance in a wide range of tumors and the development of therapies that target these apoptosis modulators appears to be a promising approach [39], [40]. Two main strategies to target BCL-2 and related family members are

Targeting the IAP family

The IAP family comprises a group of eighth structurally related proteins that share the presence of one or three zinc-binding motifs named the baculovirus IAP repeat (BIR) domain [65]. They constitute a functionally heterogeneous family and two members of the family, XIAP and survivin, are particularly involved in the inhibition of apoptosis. XIAP has three BIR domains that can interact and interfere with caspases-9, -3, and -7 activity. The BIR3 domain is involved in caspase-9 inhibition and

Apoptosis targeting strategies in clinical studies

Based on the promising preclinical results a number of therapeutic strategies that target the extrinsic or intrinsic pathway of apoptosis are being explored in early clinical studies in lung cancer. Agents that are most likely to produce approved products in the near future are TRAIL receptor targeted agents in NSCLC, antagonising inhibitors of XIAP or survivin and inhibition of the BCL-2 family of proteins both in NSCLC and SCLC (see Fig. 1). A summary of ongoing and completed clinical studies

Conclusions and future perspectives

Apoptosis targeting agents have shown promising anti-tumor activity in preclinical lung cancer models. Some of the agents appear to be particularly effective in either NSCLC or SCLC. For example, TRAIL receptor targeted agents are only tested in NSCLC patients, since DISC formation in SCLC is generally impaired. On the other hand, BCL-2 targeting agents as monotherapy display preferential activity for SCLC. The apoptotic drugs seem to be promising especially in combination with traditional

Conflict of interest

Milind M. Pore, T. Jeroen Hiltermann and Frank A.E. Kruyt have nothing to disclose.

Acknowledgements

FAEK is supported by the Dutch Cancer Society KWF-NK Grant 2006-3567 and Project T3-112 of the Dutch Top Institute Pharma.

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