Convergence of pathway analysis and pattern recognition predicts sensitization to latest generation TRAIL therapeutics by IAP antagonism

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.

The multifaceted role of TRAIL signaling in cancer and immunity

“…Recently, the expression patterns of the regulators involved in TRAIL pathway were used to develop a list of 11 markers that can predict, with 80-100% accuracy, the sensitivity of a melanoma cancer cell towards a combined therapy with TRAIL-R agonist and IAP antagonist. [256]. Thus, a successful future therapy comprises a combination of TRAIL signaling activator with strategies to prevent induction of resistance.…”

Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma

“…Beyond GBM, the CNS is also a frequent secondary site for many cancer metastases, including lung cancer, breast cancer and melanoma, consequently leading to lower treatment responses and poor patient outcomes [50,51]. Therefore, a CNS-targeted therapeutic variant of TRAIL, which shows broad anti-cancer efficacy in various cancer types [15,16,52,53] would be of considerable clinical interest as an anti-cancer agent. Furthermore, recent studies have suggested that endogenous TRAIL plays an important role in immune modulation in multiple sclerosis [54], suggesting a CNS-targeted TRAIL variant could also be used in the treatment of multiple sclerosis and other inflammatory CNS disorders [55,56].…”

“…Fc-scTRAIL is a second-generation TRAIL-receptor agonist, produced by fusion of a singlechain TRAIL (scTRAIL) trimer to the Fc region of an IgG, resulting in an overall hexavalent TRAIL-receptor agonist that potently engages TRAIL receptor-mediated apoptosis in a wide range of cancer cells [12][13][14][15][16]. The penetration of large biologics, such as TRAIL, into the CNS, is generally prevented by the presence of the blood-brain barrier (BBB), with approximately 0.1% of injected antibody doses reaching the brain parenchyma [17][18][19].…”

A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells

“…CellTrace CFSE Cell Proliferation Kit (C34554) was purchased from Thermo Fisher Scientific. FaDu, BT-474, HCT116, HT1080, WM1791c and MCF-7 cells were obtained from different sources and cultured as described previously 36 , 68 – 70 . LIM1215 were obtained from Merck KGaA (10092301-1VL), SW-620 cells and MDA-MB-231 cells were obtained from CLS Cell Lines Service GmbH (300466), respectively, and cultured in RPMI-1640 (Thermo Fisher Scientific, 11875), 10% FBS (Pan Biotech, P30-3309).…”