Therapeutic targeting of TRAIL death receptors

Abstract

The discovery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) along with its potent and selective antitumor effects initiated a decades-long search for therapeutic strategies to target the TRAIL pathway. First-generation approaches were focused on the development of TRAIL receptor agonists (TRAs), including recombinant human TRAIL (rhTRAIL) and TRAIL receptor-targeted agonistic antibodies. While such TRAIL pathway-targeted therapies showed promise in preclinical data and clinical trials have been conducted, none have advanced to FDA approval. Subsequent second-generation approaches focused on improving upon the specific limitations of first-generation approaches by ameliorating the pharmacokinetic profiles and agonistic abilities of TRAs as well as through combinatorial approaches to circumvent resistance. In this review, we summarize the successes and shortcomings of first- and second-generation TRAIL pathway-based therapies, concluding with an overview of the discovery and clinical introduction of ONC201, a compound with a unique mechanism of action that represents a new generation of TRAIL pathway-based approaches. We discuss preclinical and clinical findings in different tumor types and provide a unique perspective on translational directions of the field.

Keywords: Eftozanermin alfa; ONC201; TLY012; TRAIL; apoptosis; cancer.

Figure 1.. Cell death signaling activated by TRAIL and TRAIL pathway therapeutics.

TRAIL pathway signaling is initiated upon TRAIL binding to DR4 or DR5, driving receptor trimerization and recruitment of the FADD to form the DISC. DR4 and DR5 compete with decoy receptors DcR1, DcR2, and the soluble OPG for TRAIL. Activation of DR4 or DR5 triggers apoptotic signaling initially through initiator caspases, primarily caspase-8. Extrinsic apoptotic signaling (blue arrows) continues through activation of executioner caspases-3, -6, and -7, resulting in apoptotic death. Caspase-8 additionally activates intrinsic apoptotic signaling (green arrows) through facilitating conversion of Bid to tBid, driving proapoptotic factor release from the mitochondrion, apoptosome assembly, and ultimately also converging on executioner caspase activation. Several therapies, as described in the text, have been developed to engage at several points along this path (red labels and red arrows). Some, including first and second generation rTRAIL, TRAs, and antibodies, directly agonize DR4 and DR5 (unless otherwise indicated, these agonists have described activity against both DR4 and DR5). Downstream, inhibitors of c-FLIP prevent its competition with pro-caspase-8 for the FADD to enhance caspase-8 activation. Bcl-2 family inhibitors act to mitigate the function of antiapoptotic members of the Bcl-2 family, especially Bcl-2 and Bcl-xL. Smac mimetics also help to sequester anti-apoptotic IAPs. On a transcriptional level, ONC201 (initially referred to as TIC10 for TRAIL-inducing compound 10) antagonizes DRD2 and DRD3 while agonizing ClpP, ultimately bringing about growth arrest through the integrated stress response (ISR). Moreover, downstream effects of ONC201 (alongside p53) drive increased expression of TRAIL and DR5. Pointed arrows indicate activation; blunted arrows indicate inhibition.