The TRAIL to cancer therapy: Hindrances and potential solutions

https://doi.org/10.1016/j.critrevonc.2019.08.008 Get rights and content

Highlights

  • Dysregulation of TRAIL-induced apoptosis contributes to carcinogenesis.

  • TRAIL and TRAIL receptor agonists are proven safe and tolerable at clinical trials.

  • TRAIL is potentially to be delivered via gene therapy.

  • Sensitizers could be used to enhance TRAIL-induced apoptosis.

Abstract

Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. Resistance to apoptosis is a hallmark of virtually all malignancies. Despite being a cause of pathological conditions, apoptosis could be a promising target in cancer treatment. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of TNF cytokine superfamily. It is a potent anti-cancer agent owing to its specific targeting towards cancerous cells, while sparing normal cells, to induce apoptosis. However, resistance occurs either intrinsically or after multiple treatments which may explain why cancer therapy fails. This review summarizes the apoptotic mechanisms via extrinsic and intrinsic apoptotic pathways, as well as the apoptotic resistance mechanisms. It also reviews the current clinically tested recombinant human TRAIL (rhTRAIL) and TRAIL receptor agonists (TRAs) against TRAIL-Receptors, TRAIL-R1 and TRAIL-R2, in which the outcomes of the clinical trials have not been satisfactory. Finally, this review discusses the current strategies in overcoming resistance to TRAIL-induced apoptosis in pre-clinical and clinical settings.

Introduction

Despite remarkable advances in the understanding the biology of cancer and the development of novel diagnostic and therapeutic strategies, cancer still remains as one of the major causes of death (De Miguel et al., 2016). To date, besides the surgical resection of the tumour, the central pillars of cancer therapy are the conventional radiotherapy and chemotherapy (De Miguel et al., 2016). The goal of cancer therapy is to promote the death of cancer cells without causing too much damage to the normal cells (Gerl and Vaux, 2005). However, these cancer therapies lack of cancer specificity, which might damage the normal and healthy cells, results in severe side effects with dose-limiting toxicities (De Miguel et al., 2016). Targeted cancer therapy with the use of either monoclonal antibodies (mAbs), small molecule inhibitors or immunotoxins is emerging as a promising therapeutic strategy due its specificity towards cancer cells (Baudino, 2015). However, it is limited by the development of resistance (Aldeghaither et al., 2019).

The limitations of the current cancer therapy have provided scientists with the impetus to research for alternatives. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of TNF cytokine superfamily. TRAIL has the ability to induce apoptosis via cross-linking with TRAIL-Receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), expressed by a wide variety of cancer cells, sparing the vital normal cells (Walczak et al., 1997). The discovery of this unique property among TNF superfamily members has laid the foundation for the testing of the clinical potentials of TRAIL-R-targeting therapies in cancer clinics (De Miguel et al., 2016). However, the validity of TRAIL-based cancer therapies still awaits to be established, as most cancer cells are TRAIL-resistant (Huang et al., 2016) or develop resistance after multiple treatments.

The specific cancer-targeting capability of TRAIL has attracted great attention worldwide as a potential candidate for cancer therapy. However, in light of the current limitations of TRAIL-induced apoptosis, strategies to overcome the resistance towards TRAIL-induced apoptosis have been developed progressively.

This review summarizes the mechanisms of TRAIL-induced apoptosis via extrinsic and intrinsic apoptotic pathways. It also reviews the mechanisms of cancer cell resistance towards TRAIL-induced apoptosis. Lastly, it discusses the current therapeutic strategies of recombinant human TRAIL (rhTRAIL) and TRAIL receptor agonists (TRAs) against TRAIL-R4 and TRAIL-R5, as well as unraveling the novel strategies to overcome TRAIL resistance in both pre-clinical and clinical settings.

Section snippets

TRAIL and its receptors

TRAIL is a Type II transmembrane protein which belongs to the TNF family proteins (Daniels et al., 2005). TRAIL is a 20 kDa protein encoded by a gene consisting of five exons and three introns located on chromosome 3 (Snell et al., 1997; Herr et al., 1999; Jeremias et al., 1998). TRAIL is a unique protein of which its gene was cloned back in 1995 and added to the family of TNF due to its C-terminal extracellular domain homology to other members of the TNF family (Wiley et al., 1995; Marsters,

Dysregulation of TRAIL-induced apoptosis contributes to carcinogenesis

Apoptosis is an orchestrated cellular process that occurs in physiological and pathological conditions (Ngai and Wong, 2018; Wong, 2011). This process is essential in maintaining the physiological balance between cell death and cell growth (Koff et al., 2015). Dysregulation of apoptosis leads to carcinogenesis. The dysregulation of TRAIL-induced apoptosis renders the cancerous cells developing resistance towards TRAIL-induced apoptosis. The mechanisms involved in dysregulating TRAIL-induced

TRAIL clinical trials to date

As soon as TRAIL’s potential as a selective anti-cancer agent was observed in pre-clinical studies on its functionalized variants, a great deal of effort has been placed on human clinical trials of TRAIL and TRAs (Stuckey and Shah, 2013). The first of such effort was done with the soluble rhTRAIL or dulanermin on 71 patients with metastatic solid tumors in a Phase I dose-escalation study. rhTRAIL was demonstrated to be safe and well tolerated at doses up to 30 mg/kg with no observable antibody

Delivering TRAIL via gene therapy

Lessons learned from the various TRAIL resistance mechanisms and varied clinical responses have instigated the pursuit of further means of potentiating effective TRAIL therapy. As good as the different functionalizations of TRAIL and TRAs have achieved to improve tumor sensitivity towards TRAIL, the inherent lack of stability, rapid inactivation and renal clearance of TRAIL in vivo (Kim et al., 2011; Lim et al., 2011) have constrained its therapeutic potential by limiting its therapeutic window

Conclusion and future prospect

TRAIL is a precious jewel in the treasury of anti-cancer candidates. Nonetheless, as hard as it is to locate a gem in an underground treasury, it has also been an ardent process of pushing the gem of TRAIL to the clinical bench due to the issue of resistance. The resistance mechanisms which have been reviewed include the disrupted balance between the anti-apoptotic proteins, Bcl-2 family proteins, cFLIP (Zhang et al., 2004; Zang et al., 2014) and the pro-apoptotic proteins, Bax, Bak and Bok (

Funding

This work was supported by Fundamental Research Grant Scheme (FRGS/1/2016/STG05/UNIM/03/1), funded by the Ministry of Education Malaysia.

Declaration of Competing Interest

The authors declare no conflict of interest, financial or otherwise.

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