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.
Pubmed ID: 30416750 RIS Download
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Multi paradigm numerical computing environment and fourth generation programming language developed by MathWorks. Allows matrix manipulations, plotting of functions and data, implementation of algorithms, creation of user interfaces, and interfacing with programs written in other languages, including C, C++, Java, Fortran and Python. Used to explore and visualize ideas and collaborate across disciplines including signal and image processing, communications, control systems, and computational finance.
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View all literature mentionsThis monoclonal targets beta-Actin
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View all literature mentionsThis polyclonal targets FLIPalpha C-Terminal antibody produced in rabbit
View all literature mentionsThis monoclonal targets Caspase-3 (8G10) Rabbit mAb
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets PARP
View all literature mentionsThis monoclonal targets Caspase-8
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View all literature mentionsThis monoclonal targets IkappaB-alpha
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
View all literature mentionsThis monoclonal targets Akt (pan) (40D4) Mouse mAb
View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
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