2020 - Vetma - CDD.pdf (5.4 MB)
Convergence of pathway analysis and pattern recognition predicts sensitization to latest generation TRAIL therapeutics by IAP antagonism.
journal contributionposted on 2021-01-11, 16:42 authored by Vesna Vetma, Cristiano Guttà, Nathalie Peters, Christian Praetorius, Meike Hutt, Oliver Seifert, Friedegund Meier, Roland Kontermann, Dagmar Kulms, Markus RehmMarkus Rehm
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.
European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement #642295 (MELPLEX).
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy — EXC 2075 — 390740016.
German Research Foundation (FOR2036 (MO 3226/1-1))
Health Research Board Ireland (HRA POR 2015 1091)
European Union’s Horizon 2020 research and innovation programme (grant agreement #766069 (GLIO-TRAIN)
Associated research data filesSupplementary material available at: https://doi.org/10.1038/s41418-020-0512-5
CommentsThe original article is available at https://www.nature.com/
Published CitationVetma V, Guttà C, Peters N, Praetorius C, Hutt M, Seifert O, Meier F, Kontermann R, Kulms D, Rehm M. Convergence of pathway analysis and pattern recognition predicts sensitization to latest generation TRAIL therapeutics by IAP antagonism. Cell Death & Differentiation. 2020 ;27(8):2417-2432.
Publication Date21 February 2020
- Centre for Systems Medicine
- Physiology and Medical Physics
- Published Version (Version of Record)