hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma
Open accessAbstract
In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy. hvTRA is a second-generation TRAIL receptor agonist with improved composition giving increased potency, and in the present study, we showed hvTRA-induced activation of apoptosis leading to an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Furthermore, the potential of hvTRA in a clinical setting was demonstrated by showing efficacy on tumor cells harvested from melanoma patients with lymph node metastasis in an ex vivo drug sensitivity assay. Inhibition of mutated BRAF has been shown to regulate proteins in the intrinsic apoptotic pathway, making the cells more susceptible for apoptosis induction. In an attempt to increase the efficacy of hvTRA, combination treatment with the mutated BRAF inhibitor vemurafenib was investigated. A synergistic effect by the combination was observed for several cell lines in vitro, and an initial cytotoxic effect was observed in vivo. Unfortunately, the initial increased reduction in tumor growth compared with hvTRA mono treatment was not sustained, and this was related to downregulation of the DR5 level by vemurafenib. Altogether, the presented data imply that hvTRA efficiently induce apoptosis and growth delay in melanoma models and patient material, and the potential of this TRAIL receptor agonist should be further evaluated for treatment of subgroups of melanoma patients.
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Death receptors include FAS, TNFRSF1A, TNFRSF10A, and TNFRSF10B.
“Death receptors include (but are not limited to): Fas cell surface death receptor (FAS; also known as CD95 or APO-1), and TNF receptor superfamily member 1A (TNFRSF1A; best known as TNFR1), 10a (TNFRSF10A; best known as TRAILR1 or DR4), and 10b (TNFRSF10B; best known as TRAILR2 or DR5) [269, 270, 272, 273].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [273]
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- Authors
- Fleten, K. G., Flørenes, V. A., Prasmickaite, L., Hill, O., Sykora, J., Mælandsmo, G. M., & Engesæter, B.
- Affiliations
- Oslo University Hospital (NO)
- Apogenix (Germany) (DE)
- Corresponding author
- Fleten, Karianne G
- Venue
- Cell Death Discovery
- Published
- 2016-12-12
- Volume
- 2
- Issue
- 1
- Pages
- 16081-16081
- ISSN
- 2058-7716 (ISSN-L)
- PMC
- PMC5149582
- OpenAlex
- W2566291144
- Cited by
- 14
- References
- 47
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 3 · 2017: 2
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death Discovery (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Kreftforeningen (42185263650)
- Norges Forskningsråd (222262/F20)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- TRAIL receptor agonists, melanoma, apoptosis, vemurafenib, BRAF mutation, DR5, combination therapy, drug resistance, lymph node metastasis, xenograft models, tumor growth inhibition
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