Systemic network analysis identifies XIAP and I\u03baB\u03b1 as potential drug targets in TRAIL resistant BRAF mutated melanoma

Greta Del Mistro,Dagmar Kulms,Roland E Kontermann,Meike Hutt,Thomas Sauter,Ines Müller,Stefan Beissert,Anna Zinoveva,Martin Siegemund,Philippe Lucarelli,Sébastien De Landtsheer

doi:10.1038/s41540-018-0075-y

Greta Del Mistro, Dagmar Kulms + Show 9 more

Open Access

https://doi.org/10.1038/s41540-018-0075-y

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Abstract

Metastatic melanoma remains a life-threatening disease because most tumors develop resistance to targeted kinase inhibitors thereby regaining tumorigenic capacity. We show the 2nd generation hexavalent TRAIL receptor-targeted agonist IZI1551 to induce pronounced apoptotic cell death in mutBRAF melanoma cells. Aiming to identify molecular changes that may confer IZI1551 resistance we combined Dynamic Bayesian Network modelling with a sophisticated regularization strategy resulting in sparse and context-sensitive networks and show the performance of this strategy in the detection of cell line-specific deregulations of a signalling network. Comparing IZI1551-sensitive to IZI1551-resistant melanoma cells the model accurately and correctly predicted activation of NFκB in concert with upregulation of the anti-apoptotic protein XIAP as the key mediator of IZI1551 resistance. Thus, the incorporation of multiple regularization functions in logical network optimization may provide a promising avenue to assess the effects of drug combinations and to identify responders to selected combination therapies.

Highlights

Dysregulation of two major mitogen-activated pathways (RAS-RAF-MEK-ERK and PI3K-AKT-PTEN) are key drivers of melanoma development and progression,[1] with 66% of patients expressing a constitutive active mutant of the MAP-kinase BRAF.[2]
We demonstrated that the TRAIL receptor agonist IZI1551 potently induced cell death in parental mutBRAF as well as dabrafenib-conditioned mutBRAF melanoma cells lines, while sparing untransformed primary cells of the skin
Low caspase-8 levels have been reported to form non-functional heterodimers with the FLICE inhibitory protein (FLIP) that are more stable than the functional caspase-8 homodimers and may lead to NFκB activation instead of cell death induction.[29,30]

Summary

INTRODUCTION

RAF-MEK-ERK and PI3K-AKT-PTEN) are key drivers of melanoma development and progression,[1] with 66% of patients expressing a constitutive active mutant of the MAP (mitogen-activated protein)-kinase BRAF (mutBRAF, V600D or V600E).[2]. Melanoma cells were shown to stay largely resistant against conventional TRAIL treatment.[8,9] Importantly, conventional trimeric TRAIL and receptor-agonistic antibodies as single agents failed in clinical trials, due to the limited therapeutic activity in patients.[10] To overcome this therapeutic limitation we have developed novel second-generation TRAIL receptor-targeted agonists, with increased bioactivity enhancing the cytotoxic capacity towards cancer cells These fully human TRAIL-Fc-fusion proteins consist of two single-chain TRAIL molecules fused covalently to the Fc-part of human IgG, forming a potent hexameric TRAIL-receptor agonist (IZI1551). The major dysregulation identified at the acquired resistance to TRAIL we used a mixed regularization molecular level displayed downregulation of the initiator caspasescheme incorporating these two assumptions within the FALCON 8 (Fig. 2g, Figure S2a) This is due to the conditioning process in toolbox to estimate parameter values for the two cell types and which only those cells survive the constant exposure to 5 ng/ml discover the most significant changes that may confer therapy TRAIL agonist which express only low levels of caspase-8.

RESULTS

DISCUSSION

Findings

METHODS