On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics

Abstract

TRAIL and agonistic antibodies against TRAIL death receptors kill tumor cells while causing virtually no damage to normal cells. Several novel drugs targeting TRAIL receptors are currently in clinical trials. However, TRAIL resistance is a common obstacle in TRAIL based therapy and limits the efficiency of these drugs. In this review article we discuss different mechanisms of TRAIL resistance and how they can be predicted and therapeutically circumvented. In addition, we provide a brief overview of all TRAIL based clinical trials conducted so far. It is apparent that although the effects of TRAIL therapy are disappointingly modest overall, a small subset of patients responds very well to TRAIL. We argue that the true potential of targeting TRAIL death receptors in cancer can only be reached when we find efficient ways to select for those patients that are most likely to benefit from the treatment. To achieve this, it is crucial to identify biomarkers that can help us predict TRAIL sensitivity.

Increased Apoptosis Induction in Hepatocellular Carcinoma by a Novel Tumor-Targeted TRAIL Fusion Protein Combined With Bortezomib

“…23,24 These agents might be superior to other TRAIL-synergizing drugs, because inhibition of the proteasome as the central regulator of protein turnover affects multiple pathways and thus increases the likelihood that various TRAILresistance mechanisms can be bypassed. 37 BZB treatment of hepatoma cells resulted in TRAIL-R1/2 upregulation, enhanced death-inducing signaling complex formation, and down-regulation of c-FLIP and XIAP. 24 BZB not only influences the extrinsic, but also the intrinsic pathway by triggering the release of proapoptotic mitochondrial factors.…”

A fate worse than death: apoptosis as an oncogenic process

“…As discussed, many tumour types are selectively sensitive to TRAILinduced apoptosis due to selective expression (relative to many normal tissues) of TRAIL-receptor 101 . While provides therapeutic opportunities, it suggests that cancer cells must gain some advantage from expressing TRAIL receptor.…”

Identification of Mitoxantrone as a TRAIL-sensitizing agent for Glioblastoma Multiforme

“…6A, 6B). TRAIL sensitization has been shown to be linked to TRAIL receptor levels, 6,18 thus we evaluated the receptor expression levels in all 3-cell lines' upon Mitoxantrone treatment. U87MG cells have shown >10-fold increase in DR4, without any effect of Mitoxantrone on DR5 gene expression levels.…”

“…4,5 Although TRAIL has the ability to selectively kill cancer cells, 3 many cancer cells are intrinsically resistant or acquire resistance to TRAIL. While the mechanisms behind TRAIL resistance are still ill-defined, they include aberrant expression or dysregulation of apoptosis pathway components at the transcriptional level, such as the suppression of death receptors 6 or at the protein level, such as the degradation of FLIP. 7 Apoptosis resistance can be caused by reduced caspase expression, 8 increased expression of antiapoptotic molecules such as the inhibitors of apoptosis proteins (IAPs), overexpression of Bcl-2 family members and other inhibitors of intrinsic apoptosis pathway.…”

“…7 Apoptosis resistance can be caused by reduced caspase expression, 8 increased expression of antiapoptotic molecules such as the inhibitors of apoptosis proteins (IAPs), overexpression of Bcl-2 family members and other inhibitors of intrinsic apoptosis pathway. 6,9 Accumulating evidence suggest that sensitization of tumor cells to TRAIL is possible 10,11 through secondary agents. A widely studied approach for TRAIL-sensitization involves the use of secondary therapeutics in addition to TRAIL, where the timing and sequence of application of each agent might be different.…”