ArticleOncogene2015
TRAIL-R2-specific antibodies and recombinant TRAIL can synergise to kill cancer cells.
Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
41 citing papers in PubMed, 74 citations in OpenAlex.
- Antineoplastic Activity of a Novel Trispecific Single-Chain Antibody Targeting the hERG1/β1 Integrin Complex and TRAIL Receptors.Molecular cancer therapeutics · 2025Article
- Pharmacokinetics and immunogenicity of eftozanermin alfa in subjects with previously-treated solid tumors or hematologic malignancies: results from a phase 1 first-in-human study.Cancer chemotherapy and pharmacology · 2024Article
- Review of the Role of Nanotechnology in Overcoming the Challenges Faced in Oral Cancer Diagnosis and Treatment.Molecules (Basel, Switzerland) · 2023Article
- Generation of magnetic biohybrid microrobots based on MSC.sTRAIL for targeted stem cell delivery and treatment of cancer.Cancer nanotechnology · 2023Article
- Review
- Harnessing TRAIL-induced cell death for cancer therapy: a long walk with thrilling discoveries.Cell death and differentiation · 2023Review
- The benefits of clustering in TNF receptor superfamily signaling.Frontiers in immunology · 2023Review
- Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers.Cell death and differentiation · 2022Article
- Cancer nanotechnology: current status and perspectives.Nano convergence · 2021Review
- Therapeutics Targeting the Core Apoptotic Machinery.Cancers · 2021Review
- Designed proteins assemble antibodies into modular nanocages.Science (New York, N.Y.) · 2021Article
- PRDM14 mediates chemosensitivity and glycolysis in drug‑resistant A549/cisplatin cells and their progenitor A549 human lung adenocarcinoma cells.Molecular medicine reports · 2021Article
- Designed proteins assemble antibodies into modular nanocages.bioRxiv : the preprint server for biology · 2020Article
- Stress Management: Death Receptor Signalling and Cross-Talks with the Unfolded Protein Response in Cancer.Cancers · 2020Review
- Review
- Ubiquitin specific peptidase 5 promotes ovarian cancer cell proliferation through deubiquitinating HDAC2.Aging · 2019Article
- Molecular Mode of Action of TRAIL Receptor Agonists-Common Principles and Their Translational Exploitation.Cancers · 2019Review
- TRAILblazing Strategies for Cancer Treatment.Cancers · 2019Review
- Importance of TRAIL Molecular Anatomy in Receptor Oligomerization and Signaling. Implications for Cancer Therapy.Cancers · 2019Review
- Generation and characterization of novel anti-DR4 and anti-DR5 antibodies developed by genetic immunization.Cell death & disease · 2019Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells while sparing normal tissues. Despite promising preclinical results, few patients responded to treatment with recombinant TRAIL (Apo2L/Dulanermin) or TRAIL-R2-specific antibodies, such as conatumumab (AMG655). It is unknown whether this was due to intrinsic TRAIL resistance within primary human cancers or insufficient agonistic activity of the TRAIL-receptor (TRAIL-R)-targeting drugs. Fcγ receptors (FcγR)-mediated crosslinking increases the cancer-cell-killing activity of TRAIL-R2-specific antibodies in vivo. We tested this phenomenon using FcγR-expressing immune cells from patients with ovarian cancer. However, even in the presence of high numbers of FcγR-expressing immune cells, as found in ovarian cancer ascites, AMG655-induced apoptosis was not enabled to any significant degree, indicating that this concept may not translate into clinical use. On the basis of these results, we next set out to determine whether AMG655 possibly interferes with apoptosis induction by endogenous TRAIL, which could be expressed by immune cells. To do so, we tested how AMG655 affected apoptosis induction by recombinant TRAIL. This, however, resulted in the surprising discovery of a striking synergy between AMG655 and non-tagged TRAIL (Apo2L/TRAIL) in killing cancer cells. This combination was as effective in killing cancer cells as highly active recombinant isoleucine-zipper-tagged TRAIL (iz-TRAIL). The increased killing efficiency was due to enhanced formation of the TRAIL death-inducing signalling complex, enabled by concomitant binding of Apo2L/TRAIL and AMG655 to TRAIL-R2. The synergy of AMG655 with Apo2L/TRAIL extended to primary ovarian cancer cells and was further enhanced by combination with the proteasome inhibitor bortezomib or a second mitochondrial-derived activator of caspases (SMAC) mimetic. Importantly, primary human hepatocytes were not killed by the AMG655-Apo2L/TRAIL combination, also not when further combined with bortezomib or a SMAC mimetic. We therefore propose that clinical-grade non-tagged recombinant forms of TRAIL, such as dulanermin, could be combined with antibodies such as AMG655 to introduce a highly active TRAIL-R2-agonistic therapy into the cancer clinic.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.