Abstract
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.
Highlights
IntroductionBirinapant binds to and inhibits x-linked inhibitor of apoptosis protein (XIAP), a major antagonist of caspases-9, -3, -7 that is involved in upstream regulation of cell death signalling, with nM affinity [11,12,13]
The immune system can eliminate cancer cells by activating cell surface apoptosis-inducing death receptors, such as tumour necrosis factor-related apoptosis-inducing ligand receptors 1 and 2 ( known as death receptors 4 and 5Stuttgart, Stuttgart, Germany 8 Experimental Dermatology, Department of Dermatology, Technical University Dresden, Dresden, Germany 9 Stuttgart Centre for Simulation Science (SC SimTech), University of Stuttgart, Stuttgart, Germany 10 Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland (DR4/5))
To study the responsiveness and the response heterogeneities of melanoma cells to IZI1551, a novel and translationally relevant hexavalent TRAIL receptor agonist [3], to the IAP antagonist TL32711/Birinapant, a compound currently evaluated in clinical trials [21], or combinations thereof, we employed a diverse set of sixteen cell lines
Summary
Birinapant binds to and inhibits x-linked inhibitor of apoptosis protein (XIAP), a major antagonist of caspases-9, -3, -7 that is involved in upstream regulation of cell death signalling, with nM affinity [11,12,13]. Inducing apoptosis through the TRAIL pathway can proceed without the need for transcriptional responses or protein neo-synthesis, processes required for cell death induction by the majority of cytotoxic therapeutics. This suggests that pre-treatment amounts of proteins regulating apoptotic TRAIL signalling might suffice to derive predictors for treatment responsiveness
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