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http://dx.doi.org/10.18419/opus-13244
Autor(en): | Vetma, Vesna Guttà, Cristiano Peters, Nathalie Praetorius, Christian Hutt, Meike Seifert, Oliver Meier, Friedegund Kontermann, Roland Kulms, Dagmar Rehm, Markus |
Titel: | Convergence of pathway analysis and pattern recognition predicts sensitization to latest generation TRAIL therapeutics by IAP antagonism |
Erscheinungsdatum: | 2020 |
Dokumentart: | Zeitschriftenartikel |
Seiten: | 2417-2432 |
Erschienen in: | Cell death & differentiation 27 (2020), S. 2417-2432 |
URI: | http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-ds-132635 http://elib.uni-stuttgart.de/handle/11682/13263 http://dx.doi.org/10.18419/opus-13244 |
ISSN: | 1350-9047 1476-5403 |
Zusammenfassung: | Second generation TRAIL-based therapeutics, combined with sensitising co-treatments, have recently entered clinical trials. However, reliable response predictors for optimal patient selection are not yet available. Here, we demonstrate that a novel and translationally relevant hexavalent TRAIL receptor agonist, IZI1551, in combination with Birinapant, a clinically tested IAP antagonist, efficiently induces cell death in various melanoma models, and that responsiveness can be predicted by combining pathway analysis, data-driven modelling and pattern recognition. Across a panel of 16 melanoma cell lines, responsiveness to IZI1551/Birinapant was heterogeneous, with complete resistance and pronounced synergies observed. Expression patterns of TRAIL pathway regulators allowed us to develop a combinatorial marker that predicts potent cell killing with high accuracy. IZI1551/Birinapant responsiveness could be predicted not only for cell lines, but also for 3D tumour cell spheroids and for cells directly isolated from patient melanoma metastases (80-100% prediction accuracies). Mathematical parameter reduction identified 11 proteins crucial to ensure prediction accuracy, with x-linked inhibitor of apoptosis protein (XIAP) and procaspase-3 scoring highest, and Bcl-2 family members strongly represented. Applied to expression data of a cohort of n = 365 metastatic melanoma patients in a proof of concept in silico trial, the predictor suggested that IZI1551/Birinapant responsiveness could be expected for up to 30% of patient tumours. Overall, response frequencies in melanoma models were very encouraging, and the capability to predict melanoma sensitivity to combinations of latest generation TRAIL-based therapeutics and IAP antagonists can address the need for patient selection strategies in clinical trials based on these novel drugs. |
Enthalten in den Sammlungen: | 04 Fakultät Energie-, Verfahrens- und Biotechnik |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | |
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s41418-020-0512-5.pdf | 5,54 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons