The TRAIL to cancer therapy: Hindrances and potential solutions
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.
References (193)
- et al.
Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy
Cytokine Growth Factor Rev.
(2003) Targeting the extrinsic apoptosis pathway in cancer
Cytokine Growth Factor Rev.
(2008)- et al.
Cellular FLICE-inhibitory protein (c-FLIP) signalling: a key regulator of receptor-mediated apoptosis in physiologic context and in cancer
Int. J. Biochem. Cell Biol.
(2010) TRAIL-induced survival and proliferation of SCLC cells is mediated by ERK and dependent on TRAIL-R2/DR5 expression in the absence of caspase-8
Lung Cancer
(2008)A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma
Ann. Oncol.
(2016)- et al.
c-FLIP knockdown induces ligand-independent DR5-, FADD-, caspase-8-, and caspase-9-dependent apoptosis in breast cancer cells
Biochem. Pharmacol.
(2008) The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain
Immunity
(1997)First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: a Phase I/II open-label and double-blind study
Eur. J. Cancer
(2012)Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL
J. Biol. Chem.
(1998)- et al.
TRAIL signalling: decisions between life and death
Int. J. Biochem. Cell Biol.
(2007)
Smac mimetics activate the E3 ligase activity of cIAP1 protein by promoting RING domain dimerization
J. Biol. Chem.
c-FLIPR, a new regulator of death receptor-induced apoptosis
J. Biol. Chem.
Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer
Lung Cancer
Suppression of tumor growth following intralesional therapy with TRAIL recombinant adenovirus
Mol. Ther.
Cellular inhibitor of apoptosis 1 (cIAP-1) degradation by caspase 8 during TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis
Exp. Cell Res.
Targeting Apo2L/TRAIL receptors by soluble Apo2L/TRAIL
Cancer Lett.
Apoptosis: a link between cancer genetics and chemotherapy
Cell
Targeting death receptors in cancer with Apo2L/TRAIL
Curr. Opin. Pharmacol.
Preparation and characterization of Apo2L/TNF-related apoptosis-inducing ligand-loaded human serum albumin nanoparticles with improved stability and tumor distribution
J. Pharm. Sci.
A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer
Ann. Oncol.
Adenovirus-mediated gene delivery: potential applications for gene and cell-based therapies in the new era of personalized medicine
Genes Dis.
Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis
Cell
Six1 mediates resistance to paclitaxel in breast cancer cells
Biochem. Biophys. Res. Commun.
A mechanism of resistance to antibody-targeted immune attack
Cancer Immunol. Res.
XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells
Mol. Cancer Ther.
Targeting death and decoy receptors of the tumour-necrosis factor superfamily
Nat. Rev. Cancer
Death-receptor activation halts clathrin-dependent endocytosis
Proc Natl Acad Sci U S A
Targeted cancer therapy: the next generation of cancer treatment
Curr. Drug Discov. Technol.
Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival
Cancer Res.
Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine
Cancer Res.
A multicenter randomized phase II trial of Mapatumumab, a TRAIL-R1 agonist monoclonal antibody, in combination with bortezomib in patients with relapsed/refractory multiple myeloma (MM)
Blood
A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells
Oncogene
A cell-based high-throughput screen to identify synergistic TRAIL sensitizers
Cancer Immunol. Immunother.
Divergent roles for TRAIL in lung diseases
Front. Med. (Lausanne)
A phase I safety and pharmacokinetic study of the death receptor 5 agonistic antibody PRO95780 in patients with advanced malignancies
Clin. Cancer Res.
XIAP and survivin as therapeutic target’s for radiation sensitization in preclinical models of lung cancer
Oncogene
Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis
Cell Death Differ.
Mislocalisation of death receptors correlates with cellular resistance to their cognate ligands in human breast cancer cells
Oncotarget
Six1 overexpression in mammary cells induces genomic instability and is sufficient for malignant transformation
Cancer Res.
Impact of natural products on developing new anti-cancer agents
Chem. Rev.
Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy
Nat. Rev. Mol. Cell Biol.
Expression of TRAIL and TRAIL receptors in normal and malignant tissues
Cell Res.
Onto better TRAILs for cancer treatment
Cell Death Differ.
The BCL-2 protein family, BH3-mimetics and cancer therapy
Cell Death Differ.
RING domain E3 ubiquitin ligases
Annu. Rev. Biochem.
Accumulation of autophagosomes in breast cancer cells induces TRAIL resistance through downregulation of surface expression of death receptors 4 and 5
Oncotarget
Phase 1 study of conatumumab, a pro-apoptotic death receptor 5 agonist antibody, in Japanese patients with advanced solid tumors
Cancer Chemother. Pharmacol.
N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death
Cell Death Differ.
Targeting inhibitor of apoptosis proteins in combination with dacarbazine or TRAIL in melanoma cells
Cancer Biol. Ther.
Novel HTS strategy identifies TRAIL-sensitizing compounds acting specifically through the caspase-8 apoptotic axis
PLoS One
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